JP2004501185A - Topical pharmaceutical formulations and treatments - Google Patents
Topical pharmaceutical formulations and treatments Download PDFInfo
- Publication number
- JP2004501185A JP2004501185A JP2002504985A JP2002504985A JP2004501185A JP 2004501185 A JP2004501185 A JP 2004501185A JP 2002504985 A JP2002504985 A JP 2002504985A JP 2002504985 A JP2002504985 A JP 2002504985A JP 2004501185 A JP2004501185 A JP 2004501185A
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- JP
- Japan
- Prior art keywords
- pharmaceutical formulation
- therapeutic agent
- carrier medium
- skin
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960004869 thiethylperazine Drugs 0.000 description 1
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- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
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- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
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- 229960003904 triflupromazine Drugs 0.000 description 1
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- 235000019166 vitamin D Nutrition 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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Abstract
本発明は、治療剤の治療上の有効な単位用量およびその製薬学的に許容可能な担体媒体からなり、哺乳動物患者の皮膚と連続して接触させておいた時に、10分未満の時間内に該治療剤の単位用量を哺乳動物患者の所望の皮膚面積に実質的に塗布するための粘稠度に軟化するように、周囲温度で固形状であり、35℃以下の軟化点を有する哺乳動物に局所投与するための医薬製剤に関する。The present invention comprises a therapeutically effective unit dose of a therapeutic agent and its pharmaceutically acceptable carrier medium, which, when in continuous contact with the skin of a mammalian patient, has a duration of less than 10 minutes. The mammal is solid at ambient temperature and has a softening point of 35 ° C. or less so that the unit dose of the therapeutic agent softens to a consistency for substantially applying to the desired skin area of the mammalian patient. Pharmaceutical formulations for topical administration to animals.
Description
【0001】
この発明は、動物の患者に治療剤を皮膚投与するための医薬製剤(pharmaceutical formulations)、それを含有する医薬品(pharmaceutical products)ならびにそのような医薬製剤および医薬品を使用する治療法に関する。
皮膚感染等のような局所疾患の治療において、多くの場合、局所または局部的な効果を有する形態での治療剤を処方することが望ましい。局所製剤は、クリーム、軟膏、液剤、ローション剤、懸濁剤、パスタ剤、乳剤、気泡剤等を含む様々な形態で入手可能である。水混和性クリームは、一般的に、湿潤性または滲出性損傷に使用されるのに対し、軟膏は、一般的に、乾燥性、苔筵性または鱗状損傷もしくはより閉塞作用が必要である場合に選択される。ローション剤は、一般的に、広い部分または髪の生えている部分への最小限の塗布が必要な場合または滲出性損傷の治療に有効である。
いかなる投与計画でも、正確な投与を行うことが重要であり、実質的に上述されるような局所製剤の場合、患者が注意深く指示に従うことによって副作用を避けることが特に重要である。例えば、一般に、使用に必要な製剤の正確な量を知ることが困難なため、そのような局所製剤で、誤って推奨用量よりも容易に高用量に達するかもしれない。
身体の特定部位に従来処方される局所製剤の適切な量は、以下のとおりである:
【0002】
【表1】
【0003】
上記の量は、通常、成人にとって1日2回、1週間の塗布に適している。しかし、上述した推奨は全ての局所製剤に適用できず、局所製剤の多くの種類は、専門の投与計画が必要である。例えば、上述した推奨はコルチコステロイド製剤には適用できない。さらに詳しくは、強力なコルチコステロイド製剤について、皮膚経路の吸収は、重篤な脳下垂体‐副腎系の抑制およびクッシング症候群を引き起こすかもしれず、その双方とも処置される身体の面積および治療期間に依存するため、塗布する際に細心の注意が必要である。したがって、コルチコステロイド製剤は、通常、1日に1回または2回塗布し(それらを頻繁に塗布する必要はない)、身体の特定部位に従来処方される適切な量は、以下のとおりである:
【0004】
【表2】
【0005】
さらに、手足または身体の重篤なアトピー性湿疹(または軽症から中程度の湿疹の発症)の治療は、多くの場合、依然としてさらなる配慮が必要である。例えば、治療は、場合によっては最初の1〜2週間、強力にまたは適度に効くコルチコステロイドの塗布が必要であり、次いで、状態が改善するにつれて弱い製剤にする。皮膚軟化剤も使用される。
局所製剤の以下の投与計画に細心の注意が必要であり、考慮されるべき特別な配慮は、治療の経過中、どのような治療剤にとっても許容できる極量であることは、上記から正しく認識できるであろう。例えば、以下は、特別な投与計画、特に極量が指示される先行技術の局所製剤の特定の例である。例は、以下である:
−塩酸ドキセピン、通常、1回の塗布につき最大3gの投与で、1日に3〜4回、薄く塗布するよう推奨され、1日に12gの最大投与で、適切な適用範囲は身体表面の約10%未満であるべきである、
−プロピオン酸クロベタゾール、通常、1週間につき、0.05%製剤の約50gの最大投与で、4週間まで、1日に1〜2回薄く塗布するよう推奨される、
−吉草酸ジフルコルトロン、通常、1週間につき、0.3%製剤の約60gの最大投与で、4週間(0.1%製剤)または2週(0.3%製剤)まで、1日に1〜2回塗布するよう推奨される。
【0006】
特に、極量がモニターされるべきであることはカルシポトリオール(Calcipotriol)の局所製剤について、特に重要であることが分かってきた。例えば、カルシポトリオールの推奨される1週間の極量が限度を越えると、高カルシウム血症の危険性があることが分かってきた。不運にも、上述することは、カルシポトリオールの局所製剤が提供される患者の情報で必ずしも常に明確に説明されない。前記の高カルシウム血症の可能性に拘わらず、例えば、登録商標ドボネクス(Dovonex)で入手可能なカルシポトリオールの局所製剤は、自由な適用を勧めているので、理解され得るように、上述することは問題が多い。しかし、カルシポトリオールの局所製剤の推奨される投与計画は、1週間の極量が100gで、1日に1または2回適用されるべきである。6歳以上の患者には、製剤は1日に2回塗布し、6〜12歳の患者は1週間の極量が50gで、12歳以上の患者は1週間の極量が75gであるべきである。
【0007】
皮膚投与用の治療剤の極量を観察することが重要である治療計画が直面する問題を解決するために、そのような治療剤を患者に実質的に正確に皮膚投与するための手段を提供できることは有益であろう。そのような正確な投与で、極量が限度を越える場合に、従来観察された有害な副作用を回避するべきである。
過去に、上述した正確な投与を行うよう試みた時に直面する困難は、治療剤が局所製剤で皮膚に投与される場合に生じ、さらにそのような局所製剤の正確な量を測定することができることは患者にとって問題である。したがって、患者が治療剤の正確な用量を投与したか確認することは特に困難である。そのような局所製剤で患者の皮膚に塗布される治療剤の量を計量または投与する1つの方法は、患者がチューブのようなディスペンサーからそのような局所製剤を人差し指の指先から第1関節まで搾り出すことである。そのように投与すべき治療剤の量は指先単位(FTU)として知られている。一般的に、1FTUは、局所製剤の約500mgに近く、一般的に、成人の掌の2倍の面積を覆うのに十分である。しかし、そのような投与では正確な投与量は従来得られなかった。特に、上述されたことは、FTUが唯一の適切な単位で、その量は患者によって変化するという点で問題である。
【0008】
さらに、患者の皮膚に治療剤を含有する粘着性パッチを貼ることによって治療剤を経皮的に投与することが知られている。そのようなパッチは、通常、速度緩和膜、接着剤、裏地および裏うち材をさらに含む。接着剤は、そのようなパッチの他成分との適合性を確保する特別な処方が必要であり、この種の処方はしばしばパッチの費用を増加させる。さらに、全ての治療剤がそのようなパッチへの含有に適しているとは限らないので(通常、局部治療効果を有する治療剤は従来そのようなパッチに使用されていない)、そのようなパッチの使用では、そのような治療剤の皮膚投与が可能なルートは提供されなかった。
また、そのようなパッチは、製薬学的分野において「医薬プラスター」と呼ばれている。例えば、米国特許第4765986号には、担体物質に存在する薬物からなる医薬プラスターが記載されており、この担体物質は、多孔性で柔軟な合成材料に貼付される。
【0009】
さらに、米国特許第5863941号は、治療剤の皮膚投与に関するもので、特に、内耳の病理学的症状の治療法を述べている。より詳しくは、米国特許第5863941号には、担体物質および治療剤の使用について述べており、後者は、担体物質の約0.5〜40重量%量に存在する局所麻酔薬を含む。内耳治療に使用するための米国特許第5863941号に記載の担体物質および治療剤は、米国特許第4765986号に記載の形態をとってもよい。
液状での供給に適した治療剤の皮膚投与について、欧州特許第EP0375763B号は、医薬溶液のような液体を患者の皮膚に投与するための塗布器について述べている。欧州特許第EP0375763B号で記載されている器具は、その内部空洞が変形し得るマイクロメトリック・スクリュー投与メカニズムを備える。しかし、欧州特許第EP0375763B号に記載された種類の塗布器は、当然ながら溶液で供給することができる治療剤の使用にのみ適している。
本発明は、従来技術の改良であり、1以上の治療剤を動物患者に、皮膚投与するのに適した医薬製剤、それを含有する医薬品、そのような医薬製剤および医薬品の製造方法、ならびにそのような医薬製剤および医薬品を用いた動物患者の治療方法を提供する。特に、本発明は、医薬製剤、それを含有する医薬品、そのような医薬製剤および医薬品の製造方法および治療方法を提供し、それらはそれぞれ1以上の治療剤を動物患者の皮膚に正確に投与することができる。
【0010】
ある実施形態において、本発明は、治療剤の治療上の有効量の単位用量およびその製薬学的に許容可能な担体媒体を含む、哺乳動物への局所投与用医薬製剤に関し、この医薬製剤は、室温で固形であり、35℃以下の軟化点を有し、哺乳動物の患者の皮膚と連続して接触させておかれた場合に、10分未満の時間内で治療剤の単位用量が哺乳動物の患者の所望の皮膚面積へ実質的な塗布をもたらす粘稠度に軟化する。
本発明のある実施形態は、治療剤の治療上の有効量の単位用量およびその製薬学的に許可可能な担体媒体を含む、哺乳動物への局所投与用医薬製剤に関し、この医薬製剤は、哺乳動物の患者の皮膚温度以下の軟化点を有し、1:1(壁面:表面)より低いアスペクト比を有する。
ある実施形態は、治療剤の治療上の有効量の単位用量およびその製薬学的に許容可能な担体媒体を含む、哺乳動物への局所投与用医薬製剤に関し、この製剤は、哺乳動物の患者の皮膚と連続して接触させておいた場合に、10分未満の時間内で治療剤の単位用量が哺乳動物の患者の所望の皮膚面積へ実質的な塗布をもたらす粘稠度に軟化する。
ある実施形態は、治療剤の単位用量の成形された顆粒およびその製薬学的に許容可能な担体媒体を含む、哺乳動物への局所投与用医薬製剤に関し、この成形顆粒は、哺乳動物の患者の皮膚温度以下の軟化点を有する。
ある実施形態では、製剤は薬物の局所投与を容易にするような形状を有する。例えば、製剤は、少なくとも1つの平面、少なくとも1つの凹面、少なくとも1つの凸面、2つの平面、2つの凹面または2つの凸面を有していてもよい。製剤の形状は、標準の錠剤、球状または半球状の形態であってもよい。弾丸状および円錐形の製剤は本発明には好ましくない。
【0011】
好ましい実施形態では、本発明の製剤は、約50mg〜1g未満、好ましくは約100〜900mg、より好ましくは約250〜750mgの総重量を有する。本発明の製剤は、望むならば、1gより重くてもよい。
人間の患者に好ましい医薬製剤では、剤形は人間の正常な外面温度(皮膚温度)以下の軟化点を有する。この温度は、通常、約35℃以下である。ある実施形態では、医薬製剤は約30〜35℃以下の軟化点を有する。
ある実施形態は、哺乳動物の患者の局所投与に適した少なくとも1つの治療剤の単位用量を含有する医薬製剤に関し、この医薬製剤は、最終的な製造中に固形となり、哺乳動物の患者の皮膚面積に塗布する前は、皮膚面積への塗布に適した拡散粘稠度を有し、この医薬製剤は、単位用量を投薬するために取り外し可能または崩壊可能な内容物を有するプラスチック容器に個々に収容される。
ある実施形態では、剤形は、製薬学的に許容可能な担体媒体と混合された治療剤からなる、複数の実質的に分離した実質的に固形状の粒子であってもよく、この粒子は、約30〜35℃の軟化点を有する。粒子はサッシェ、カプセルまたはこの粒子の単位用量を投薬するのに適した容器に封入することができる。
【0012】
ある実施形態において、本発明は動物の患者に皮膚投与するための、少なくとも1つの治療剤の単位用量を含有する医薬製剤の製造方法を導く。その方法は、以下から構成される:
(a)少なくとも1つの治療剤をその担体媒体と混合して、それらの混合物を得、(b)ステップ(a)で得られた混合物の少なくとも一部を成形し、1:1(壁面:表面)より低いアスペクト比を有する固形状製剤を得、その結果得られた製剤は、哺乳動物の皮膚温度以下の軟化点を有し、哺乳動物患者の皮膚と連続して接触させておかれると、10分未満の時間内に治療剤の単位用量を哺乳動物患者の所望の皮膚面積に実質的に塗布するための粘稠度に軟化する。
【0013】
他の実施形態は、哺乳動物患者に局所投与するのに適した少なくとも1つの治療剤を局所投与するのに有効な医薬製剤を製造する方法を導く。医薬製剤は治療剤の単位用量を含有し、周囲温度で実質的に固形状の剤形を有し、哺乳動物患者に治療剤の単位用量を投与するために、哺乳動物患者の皮膚面積に医薬製剤を塗布した時に皮膚面積で吸収され得る粘稠度に軟化可能である。その方法は、順序が特定されている以下のステップからなる:
(a)哺乳動物患者に局所投与するのに適した少なくとも1つの治療剤およびその担体媒体を提供するのに適した少なくとも1つの成分を混合して、その混合物を得、
(b)ステップ(a)で得られた混合物を冷却して、それを実質的に凝固させ、
(c)ステップ(b)で得られた実質的に凝固した混合物の少なくとも一部を成形し、少なくとも1つの治療剤の単位用量を含有する実質的に固形状の剤形を提供する。
他の実施形態は、哺乳動物患者に皮膚投与するのに適した局所医薬製剤の単位用量の製造方法を導く:
(a)治療剤をその製薬学的に許容可能な少なくとも1つの担体媒体と混合して、それらの混合物を得、
(b)ステップ(a)で得られた混合物を約15℃以下の温度に冷却し、ステップ(b)で得られた冷却混合物は半固形状の治療剤の単位用量を得るためのものである。その医薬製剤は、動物患者の皮膚面積に塗布する前に、周囲温度で、動物の患者の皮膚面積への塗布に適した拡散粘稠度を有する。
したがって、本発明は、少なくとも1つの治療剤の単位用量を含有する動物患者に皮膚投与するための医薬製剤の製造方法を提供し、その方法は以下から構成される:
(a)少なくとも1つの治療剤をその担体媒体と混合して、それらの混合物を得、
(b)ステップ(a)で得られた混合物の少なくとも一部を成形し、この医薬製剤を得る。
さらに詳しくは、本発明は少なくとも1つの治療剤の単位用量を含有し、動物の患者に皮膚投与するのに適した少なくとも1つの治療剤を皮膚投与するための医薬製剤の製造方法を提供し、その工程は以下から構成される:
(a)少なくとも1つの治療剤をその担体媒体と混合して、それらの混合物を得、
(b)ステップ(a)で得られた混合物の少なくとも一部を成形し、ステップ(a)で得られた混合物の少なくとも一部を錠剤化して成形し、少なくとも1つの治療剤の単位用量を含有する医薬製剤を提供する。
【0014】
さらに、本発明の第1観点は、動物患者に皮膚投与するのに適した少なくとも1つの治療剤を皮膚投与するための医薬製剤の製造方法を提供し、その医薬製剤は、通常、周囲温度で実質的に固形状の剤形で、実質的に以下により詳しく記載されるような動物患者の皮膚温度以下の軟化点を有し、少なくとも1つの治療剤の単位用量を含有する。その工程は以下から構成される:
(a)少なくとも1つの治療剤を動物患者の皮膚温度以下の軟化点を有する担体媒体の大部分と混合して、それらの混合物を得、
(b)担体媒体の軟化点以下の温度で、ステップ(a)で得られた混合物の少なくとも一部を成形し、動物患者の皮膚温度以下の軟化点を有し、少なくとも1つの治療剤の単位用量を含有する実質的に固形形状(通常、実質的に固形状の剤形)を形成する。
治療剤の単位用量を含む医薬製剤を提供するために、実質的に上述されるような少なくとも1つの治療剤および担体媒体の混合物の成形は、通常、実質的に上述されるようなあらゆるステップ(a)で得られた混合物の少なくとも一部の錠剤化からなる。通常、ここに記載されるような「錠剤化」は、少なくとも1つの治療剤の混合物の少なくと一部および本発明によって製造された担体媒体をタブレット成形機に導入し、導入した混合物を圧縮して、実質的に固形形状をもたらすことからなり得る。通常、実質的に固形状の剤形は、ここに実質的に記載されるような少なくとも1つの治療剤を皮膚投与するのに適した大きさおよび形態を有する。実際に、技術水準の一部を既に形成しているので、治療剤を含有する錠剤は、経口伝達用の医薬製剤の一般的な形状で、精巧に分配された成分の混合物を圧縮して製造され、用量の比較的正確さおよび再現性、所望の取扱特性および一般的に比較的安価な製造工程を考慮して有利であることが公知である。しかし、少なくとも1つの治療剤の単位用量を動物患者に皮膚投与するための本発明の錠剤は、技術水準の一部を形成しないが、実質的に上述されるような経口投与用の公知の錠剤に関連する利点を同様に有している。
【0015】
本発明の医薬製剤の製造方法は、さらに、実質的に上述されるように製造される少なくとも1つの治療剤およびその担体媒体の混合物の少なくとも一部を冷却し、その冷却により混合物の取扱特性を改善することができ、本発明によって行われるような錠剤化の速度をも増加させることができる。実質的に上述されるように、冷却は、少なくとも1つの治療剤およびその担体媒体との混合物を成形する前および/または成形の間に行われることが適切であろう。好ましくは、混合物は、実質的に上述されるように成形する前および/または成形の間に、約15℃以下の温度、有利には約10℃以下、例えば、約0℃以下に冷却することができる。
適切には、本発明の方法で行われるような冷却は、冷却された打錠機を用いることによって、少なくとも部分的になされるであろう。有利には、少なくとも1つの治療剤およびその担体媒体との混合物は、それを打錠機等に導入する前に冷却することもできる。
【0016】
本発明の第1観点による好ましい方法では、動物患者への皮膚投与に適した少なくとも1つの治療剤を皮膚投与するための医薬製剤の製造方法が提供され、その医薬製剤は、少なくとも1つの治療剤の単位用量を含有し、周囲温度で実質的に固形状の剤形を有し、動物患者に治療剤の単位用量を投与するために、動物患者の皮膚面積にその医薬製剤を塗布した時に皮膚面積で吸収され得る粘稠度に軟化することができる。その方法は、順序が特定される以下のステップから構成される:
(a)動物の患者への皮膚投与に適した少なくとも1つの治療剤およびその担体媒体の提供に適した少なくとも1つの成分を混合して、それらの混合物を得、
(b)ステップ(a)で得られた混合物を(好ましくは約10℃以下、好ましくは約0℃以下の温度で)冷却して、それを実質的に凝固させ、
(c)ステップ(b)で得られた実質的に凝固した混合物の少なくとも一部を成形し、本発明の第1観点による医薬製剤の実質的に固形形状(通常、実質的に固形状の剤形)を提供する。
通常、本発明の第1観点の方法は、実質的に固形状の剤形に成形する前に、さらに(例えば、粒状化、小球化等によって)粒子の大きさを減じる工程を含む。ステップ(b)で得られた実質的に凝固した混合物は、適切には、100〜1000ミクロン範囲の粒子の大きさの複数の粒子を提供するために粒状化することができる。
【0017】
本発明で提供される医薬製剤は、より詳しく以下に実質的に記載されるように防腐剤が実質的に存在しないことが好ましいであろう。そのような場合、本発明の工程は無菌状態下で行われることが好ましい。
さらに、本発明で提供されるような医薬製剤は、より詳しく以下に実質的に記載されるように酸化防止剤が実質的に存在しないことが好ましいかもしれない。そのような場合、本発明の方法が医薬製剤の包装を含む際、少なくともそのような包装は窒素等のような実質的に不活性雰囲気中で行われる。
また、本発明は、少なくとも1つの治療剤の単位用量およびその担体媒体を含み、動物の患者に少なくとも1つの治療剤の単位用量を皮膚投与することができる医薬製剤を提供する。
【0018】
上述される本発明の第1観点によれば、動物患者への皮膚投与に適した少なくとも1つの治療剤を皮膚投与するための医薬製剤がさらに提供され、その医薬製剤は、周囲温度で実質的に固形剤形を有し、(より詳しく以下に実質的に記載されるように)動物患者の皮膚温度以下の軟化点を有し、動物の患者への皮膚投与に適した少なくとも1つの治療剤の単位用量を含有する。
さらに詳しくは、上述される本発明の第1観点によれば、動物の患者への皮膚投与に適した少なくとも1つの治療剤を皮膚投与するための医薬製剤が提供され、その医薬製剤は、周囲温度で実質的に固形状の剤形を有し、その担体媒体と混合した少なくとも1つの治療剤を含む。その医薬製剤は、固形状剤形で特徴付けられ、動物の患者の皮膚面積にそれを塗布した時に軟化することができることによって、皮膚面積に塗布後、固形状の剤形は、動物患者に治療剤の単位用量を投与するために皮膚面積で実質的に吸収することができる粘稠度に軟化される。
さらにより詳しくは、上述される本発明の第1観点は、動物の患者への皮膚投与に適した少なくとも1つの治療剤を皮膚投与するための医薬製剤を提供し、その医薬製剤は、周囲温度で実質的に固形状の剤形を有し、その担体媒体と混合した少なくとも1つの治療剤の単位用量を含む。その製剤は、実質的に固形状の剤形で特徴付けられ、動物の患者の皮膚面積にそれを塗布する時に軟化し得ることによって、皮膚面積に塗布後、固形状の剤形は、動物の患者に治療剤の単位用量を実質的に完全に投与するために、皮膚面積で完全に吸収され得る粘稠度に軟化される。
【0019】
本発明の第1観点による周囲温度での医薬製剤の実質的に固形状の剤形は、通常、実質的に上述されるような錠剤状で提供され、通常、実質的に上述されるように製造される。あるいは、本発明の第1観点による医薬製剤の実質的に固形状の剤形は、例えば、丸剤等の丸い製剤(rolled preparation)の形状で提供されるであろう。
本発明の第1観点によれば、担体媒体、またはさらに詳しくは実質的に固形状剤形は、以下により詳しく実質的に記載されるように、上述の室温温度であるが、動物患者の皮膚温度以下の温度で(以下、拡散点と記載する)、拡散粘稠度に転化することが一般的に好ましいかもしれない。この場合、さらに、本発明の第1観点に従った方法の成形ステップは、担体媒体または実質的に固形状剤形のいずれかの拡散点以下の温度で行われることが一般的に好ましいかもしれない。
通常、本発明の第1観点による医薬製剤の担体媒体およびさらに詳しくは実質的に固形状剤形を軟化し、有利には、30〜37℃の範囲の温度で拡散粘稠度に転化することが好ましいであろう。このように、上述されるように、製剤を動物の患者の皮膚面積への塗布によって軟化し得ることにより、塗布後、製剤の実質的に固形状の剤形は、動物の患者に治療剤の単位用量を実質的に完全に投与するために、皮膚面積で実質的に完全に吸収され得る粘稠度に軟化される。
【0020】
本発明の第1観点の医薬製剤は、皮膚面積に塗布した後、約10分未満、好ましくは約5分未満、より好ましくは約3分未満、最も好ましくは約1分未満の時間内で、動物の患者に少なくとも1つの治療剤の単位用量を実質的に(好ましくは実質的に完全に)投与するために、動物の患者の皮膚面積で実質的に(好ましくは実質的に完全に)吸収され得る粘稠度に軟化できる周囲温度で、実質的に固形状剤形を有することが特に好ましい。
さらに詳しくは、実質的に固形状剤形の形状および形態は、ここに実質的に記載されるように、その軟化点で測定することが好ましい。本発明の製剤に使用される実質的に固形状剤形は、単一剤形からなり、もしくは、本発明の製剤に使用される実質的に固形状剤形は、実質的に上述されるように動物の患者の皮膚で吸収され得る(複数の顆粒等のような)実質的に分離した複数の実質的に固形状粒子からなり得ることが好ましいかもしれない。本発明の製剤に使用される実質的に固形状の剤形がここに記載されるような実質的に離散した複数粒子からなり得る場合、そのような分離粒子は、ここに実質的に記載されるように調剤でき、患者の皮膚に塗布することができる密閉部材(例えば、カプセル、サッシェ、ブリスターパッケージ等)に入れることが適切かもしれない。
【0021】
また、本発明の第1観点による医薬製剤の実質的に固形状剤形の担体媒体は、ほぼ周囲温度以上の温度で、製剤の実質的に固形状剤形への組み込みのための成形に適していることによってさらに特徴付けられることが好ましいであろう。本発明のある観点では、本発明の第1観点による製剤の実質的に固形状の剤形の担体媒体は、10℃未満、好ましくは0℃未満の温度で、製剤の実質的に固形状剤形に組み込むための成形に適していることによってさらに特徴付けられることが好ましいかもしれない。さらに詳しくは、実質的に固形状剤形の担体媒体は、10℃未満、好ましくは0℃未満の温度で、ここに実質的に記載されるような技術を用いて錠剤化するのに適していることによってさらに特徴付けられることが好ましいであろう。
好ましくは、担体媒体は、本発明の第1観点による医薬製剤の重量に基づいて、約60重量%以上、より好ましくは約80重量%以上、さらにより好ましくは約90重量%以上を構成する。
【0022】
一般に坐薬に使用されるいかなる塩基成分は、動物、野菜またはミネラル源由来の成分および部分的または全体的に合成された物質を含む本発明の医薬製剤の塩基成分として用いることができる。そのような塩基成分の特別な例は、動物または野菜源の油および脂肪、例えば、オリーブ油、コーン油、ヒマシ油、綿実油、麦芽油、カカオ脂、硬化油等;炭化水素、例えば、スクアラン、ワセリン、固形パラフィン、液体パラフィン等;およびワックス、例えば、ホホバ油、カルナバワックス、蜜蝋、ラノリン等を含む。部分的または全体的に合成された脂肪酸エステルグリセロールとして、飽和線状脂肪酸、例えば、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸等のような媒体または高級脂肪酸のモノ、ジまたはトリグリセリド、または例えば、オレイン酸、リノール酸、リノレン酸等の不飽和線状脂肪酸が挙げられる。これらの塩基成分の市販品は、(ダイナミットノーベルで製造される)ウィテップゾール、(日本油脂株式会社で製造される)ファーマゾル、(花王株式会社で製造される)イソカカオ、(太陽油脂株式会社で製造される)SB、(ヘンケルで製造される)ノバタ、(カッテフォース(Gattefosse)で製造される)スッポシア(Suppocire)等を含む。ポリエチレングリコール、例えば、マクロゴール、セトマクロゴール等並びにその誘導体、例えば、セトマクロゴールが、他の合成製品の例として挙げられる。
【0023】
本発明の医薬製剤の所望の軟化点を得るために、必要であれば、軟化点を上昇または低下させるために、塩基を、別の塩基と組み合わせることができ、適切な製品を得ることができる。例えば、軟化点を低下させるために、可塑剤として適切な塩基、例えば、グリセリルモノアセテート、ミリスチルアルコール、ポリソルベート80、プロピレングリコールまたはそれらを組み合わせたものを添加することができる。軟化点を上昇させるために、硬化剤として適した塩基、例えば、蜜蝋、セチルアルコール、ステアリン酸、ステアリルアルコール、アルミニウムモノステアレート、アルミニウムジステアレート、アルミニウムトリステアレート、ベントナイト、ステアリン酸マグネシウム、コロイド二酸化ケイ素およびそれらの組み合わせを添加することができる。
【0024】
本発明の第1観点に従って使用するための担体媒体は、実質的に上述されるように、例えば、実質的に上述されるような錠剤への使用に適し、皮膚投与に適した少なくとも1つの治療剤の単位用量を皮膚投与するための所望の特性を有するいかなる成分のような医薬製剤への使用に適したどんな成分を含んでいてもよい。例えば、担体媒体は、セルロースを含んでいてもよく、坐薬の使用に適当なタイプの成分からなる群から選択される1以上の成分(例えば、1以上の飽和脂肪酸のグリセロールエステル又は1以上のポリグリコール化(polyglycolysed)グリセリドのような1以上のグリセリド、カカオ脂、セオブローマ等を含む)、1以上の高分子量ポリエチレングリコール、1以上のポリオキシエチレン、ラノリンおよびそれらの誘導体、ならびに1以上の脂肪酸、脂肪アルコール、脂肪酸エステル(例えば、カプリル酸、トリカプリルグリセリル等を含む)、および1以上の有機油(例えば、硬化植物油を含む)等であってもよい。
本発明の第1観点の医薬製剤に用いられる担体媒体は、特に、1以上のC8−C18脂肪酸のグリセロールエステルまたは1以上のポリグリコール化グリセリドを含有する1以上のグリセリドを含むか、または実質的に構成されるのが、多くの場合好ましい。
【0025】
本発明の第1観点による医薬製剤の担体媒体は、グリセリドが1以上のモノグリセリド、ジグリセリドまたはトリグリセリドであり得る場合は、グリセリドの混合物を含むか、またはから実質的になることが適切である。適切には、グリセリド混合物は、グリセリドがC12−C18脂肪酸のグリセロールエステルであるモノグリセリド、ジグリセリドおよびトリグリセリドからなる群から選択されるグリセリドを含むことができ、ウィテップゾールグレードの製品が適切である。さらに詳しくは、担体媒体は、登録商標ウィテップゾールH5、ウィテップゾールH15、ウィテップゾールH32、ウィテップゾールS51、ウィテップゾールS55、ウィテップゾールS58、ウィテップゾールW25およびウィテップゾールW32のいずれかで入手可能なウィテップゾールグレードの製品を含むかまたはから実質的になる。本発明による医薬製剤の担体媒体として使用するための特に好ましいウィテップゾールグレードの製品は、登録商標ウィテップゾールH5、ウィテップゾールH15、ウィテップゾールS51、およびウィテップゾールS55のいずれかで入手可能であり、特に、登録商標ウィテップゾールH15で入手できる。
【0026】
本発明の第1観点による医薬品に使用される担体媒体は、実質的に上述されるようなウィテップゾールグレードの製品から実質的になることが多くの場合好ましい。
あるいは、本発明の第1観点による医薬製剤の担体媒体は、グリセリドの混合物を含むかまたはから実質的になり、グリセリドが、モノグリセリド、ジグリセリドおよびトリグリセリドからなる群から選択することができる場合、C8−C18脂肪酸のグリセロールエステルまたは1以上のポリグリコール化グリセリドを含む。適切には、そのようなグリセリド混合物は、登録商標ゲルシア(Gelucire)またはサポシア(Suppocire)で入手可能であり、通常、以下のゲルシア33/01、ゲルシア39/01、ゲルシア43/01、ゲルシア44/14のいずれか、またはサポシア標準型、サポシア N型またはサポシア P型の製品のいずれかであってもよい。
あるいは、本発明の第1観点による医薬製剤への使用に適した担体媒体は、カカオ脂を含むかまたはから実質的になる。
【0027】
本発明で使用できる活性剤は、局所または全身性のいずれかの作用のために皮膚上または皮膚を通して送り出すことができる全ての薬物を含む。これらの化合物は、主用な治療面積の全てにおいて、ACE阻害剤、腺下垂体ホルモン、アドレナリン作動性ニューロン遮断剤、副腎皮質ステロイドの生合成の抑制剤、α−アドレナリン作動薬、α−アドレナリン拮抗薬、選択性α−2−アドレナリン作動薬、鎮痛薬、解熱薬および抗炎症薬、アンドロゲン、局所および全身麻酔薬、抗耽溺剤、抗アンドロゲン、抗不整脈剤、抗喘息剤、抗コリン作動剤、抗コリンエステラーゼ剤、抗凝固薬、抗糖尿病薬、止しゃ薬、抗利尿薬、制吐薬およびプロケネティック剤(prokinetic agent)、抗てんかん剤、抗エストロゲン、抗真菌剤、血圧降下剤、抗菌剤、抗偏頭痛剤、抗ムスカリン剤、抗腫瘍剤、抗寄生虫剤、抗パーキンソン病剤、抗血小板剤、抗黄体ホルモン、抗甲状腺剤、鎮咳薬、抗ウィルス薬、異型性抗鬱薬、アザスピロデカネジオン、バルビツレート、ベンゾジアゼピン、ベンゾサイアジアザイド、β−アドレナリン作動薬、β−アドレナリン拮抗薬、選択性β−1−アドレナリン作動薬、選択性β−2−アドレナリン作動薬、胆汁酸塩、体液の体積および組成に作用する薬剤、ブチロフェノン、石灰化に作用する薬剤、カルシウム拮抗薬、心血管薬、カテコールアミンおよび交感神経興奮薬、コリン作動薬、コリンエステラーゼ再賦活化薬、外皮用剤、ジフェニルブチルピペリジン、利尿薬、麦角アルカロイド、エストロゲン、神経節遮断剤、神経節刺激剤、ヒダントイン、胃液酸度の調節剤および消化性潰瘍の治療薬剤、造血剤、ヒスタミン、ヒスタミン拮抗薬、5−ヒドロキシトリプタミン拮抗薬、高リポタンパク血症の治療薬、睡眠薬および鎮静剤、免疫抑制剤、緩下剤、メチルキサンチン、モノアミンオキシダーゼ阻害剤、神経筋遮断剤、有機硝酸塩、膵酵素、フェノチアジン、プロゲスチン、プロスタグランジン、精神障害の治療剤、レチノイド、ナトリウムチャネル遮断薬、痙性麻痺および急性筋痙攣用剤、スクシンイミド、チオキサンチン、血栓溶解剤、甲状腺剤、三環系抗鬱薬、有機化合物の尿細管輸送抑制薬、子宮運動に影響を与える薬物、血管拡張薬、ビタミン等を含む薬剤を含むが、それらに限定されるわけではない。
【0028】
一例として、代表的な薬物は、ベプリジル、ジルチアゼム、フェロジピン、イスラジピン、ニカルジピン、ニフェジピン、ニモジピン、ニトレンジピン、ベラパミル、ドブタミン、イソプロテレノール、カルテロロール、ラベタロール、レボブノロール、ナドロール、ペンブトロール、ピンドロル、プロプラノロール、ソタロール、チモロール、アセブトロール、アテノロル、ベタキソロール、エスモロール、メトプロロール、アルブテロール、ビトルテロール、イソエタリン、メタプロテレノール、ピルブテロール、リトドリン、テルブタリン、アルクロメタゾン、アルドステロン、アムシノニド、ベクロメタゾン、ジプロピオネート、ベタメタゾン、クロベタゾール、クロコルトロン、コルチゾール、コルチゾン、コルチコステロン、デゾニド、デスオキシメタゾン、11−デオキシコルチコステロン、11−デゾオキシコルチゾール、デキサメタゾン、ジフロラゾン、フルドロコルチゾン、フルニソリド、フルオシノロン、フルオシノニド、フルオロメトロン、フルランドレノリド、ハルシノニド、ヒドロコルチゾン、メドリゾン、6アルファ−メチルプレドニゾロン、モメタゾン、パラメタゾン、プレドニゾロン、プレドニゾン、テトラヒドロコルチゾール、トリアムシノロン、ベノキシネート、ベンゾカイン、ブピバカイン、クロロプロカイン、コカイン、ジブカイン、ジクロニン、エチドカイン、リドカイン、メピバカイン、プラモキシン、プリロカイン、プロカイン、プロパラカイン、テトラカイン、アルフェンタニル、コロフォーム、クロニジン、シクロプロパン、デスフルラン、ジエチルエーテル、ドロペリドール、エンフルラン、エトミデート、ハロタン、イソフルラン、ケタミン塩酸塩、メペリジン、メトヘキシタール、メトキシフルラン、モルヒネ、プロポフォール、セボフルラン、チアミラール、チオペンタール、アセトアミノフェン、アロプリノール、アパゾン、アスピリン、オーラノフィン、アウロチオグルコース、コルヒチン、ジクロフェナク、ジフルニサール、エトドラク、フェノプロフェン、フルルビプロフェン、チオリンゴ酸金ナトリウム、イブプロフェン、インドメタシン、ケトプロフェン、メクロフェナム酸、メフェナム酸、メセラミン、サリチル酸メチル、ナブメトン、ナプロキセン、オキシフェンブタゾン、フェナセチン、フェニルブタゾン、ピロキシカム、サリチルアミド、サリチル酸塩、サリチル酸、サルサラート、スルファサラジン、スリンダク、トルメチン、アセトフェナジン、クロルプロマジン、フルフェナジン、メソリダジン、ペルフェナジン、チオリダジン、トリフルオロペラジン、トリフルプロマジン、ジソピラミド、エンカイニド、フレカイニド、インデカイニド、メキシレチン、モリシジン、フェニトイン、プロカインアミド、プロパフェノン、キニジン、トカイニド、シサプリド、ドンペリドン、ドロナビノール、ハロペリドール、メトクロプラミド、ナビロン、プロクロルペラジン、プロメタジン、チエチルペラジン、トリメトベンズアミド、ブプレノルフィン、ブトルファノール、デゾシン、ジフェノキシレート、ドロコード、ヒドロコドン、ヒドロモルホン、レバロルファン、レボルファノール、ロペラミド、メプタジノール、メタドン、ナルブフィン、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、オキシブチニン、ペンタゾシン、硝酸イソソルビド、ニトログリセリン、テオフィリン、フェニレフリン、エフィドリン、ピロカルピン、フロセミド、テトラサイクリン、クロルフェニラミン、ケトロラク、ブロモクリプチン、グアナベンズ、プラゾシン、ドキサゾシンおよびフルフェナム酸を含むが、限定されるものではない。
【0029】
他の代表的な薬物は、ベンゾジアゼピン、例えばアルプラゾラム、ブロチゾラム、クロルジアゼポキシド、クロバザム、クロナゼパム、クロラゼペート、デモキセパム、ジアゼパム、フルマゼニル、フルラゼパム、ハラゼパム、ロラゼパム、ミダゾラム、ニトラゼパム、ノルダゼパム、オキサゼパム、プラゼパム、クアゼパム、テマゼパム、トリアゾラム等;抗ムスカリン剤、例えばアニソトロピン、アトロピン、クリジニウム、シクロペントレート、ジシクロミン、フラボキセート、グリコピロレート、ヘキソサイクリウム、ホマトロピン、イプラトロピウム、イソプロパミド、メペンゾレート、メタンテリン、オキシフェンシクリミン、ピレンゼピン、プロパンテリン、スコポラミン、テレンゼピン、トリジヘキセチル、トロピカミド等;エストロゲン、例えば、クロロトリアニセン、シエチルスチルベストロール、メチルエストラジオール、エストロン、エストロン硫酸ナトリウム、エストロピペート、メストラノール、キネストロール、ソディウムエキリンサルフェート、17β−エストラジオール(またはエストラジオール)、例えば、エストラジオール−17β−エナンタート、エストラジオール−17β−バルレート、エストラジオール−3−ベンゾアート、エストラジオール−17β−ウンデセノエート、エストラジオール16,17−ヘミスクシナートまたはエストラジオール−17β−シピオネートなどの天然エストロゲンのエステルのような半合成エストロゲン誘導体、およびエチニルエストラジオール、エチニルエストラジオール−3−スルホン酸イソプロピル等の17−アルキルエストロゲン等;アンドロゲン、例えば、ダナゾール、フルオキシメステロン、メトアンドロステノロン、メチルテストステロン、ナンドロロンデカノエート、ナンドロロンフェンプロピオネート、オキサンドロロン、オキシメトロン、スタノゾロール、テストラクトン、テストステロン、テストステロンシピオネート、エナント酸テストステロン、プロピオン酸テストステロン等;またはプロゲスチン、例えば、エチノジオールジアセテート、ゲストデン、カプロン酸ヒドロキシプロゲステロン、レボノルゲストレル、酢酸メドロキシプロゲス、酢酸メゲストロール、ノルエチンドロン、酢酸ノルエチンドロン、ノルエチノドレル、ノルゲストレル、プロゲステロン等を含む。
【0030】
活性薬物が局所作用を生じる実施形態では、薬剤は、抗ウィルス剤(例えば、アシクロビルおよびイドクスウリジン等)、抗真菌剤(例えば、アンフォテリシンB、クロトリマゾール、ナイスタチン、ケトコナゾール、ミコロナゾール、ブトコウアゾール、ハロプロジン等)、抗生剤(ペニシリン、セファロスポリン、エリトロマイシン、テトラサイクリン、クリンダマイシン、アミノグリコシド、クロラムフェニコール、ポリミキシンb、バシトラシン、ネオマイシン、ゲンタマイシン等)、防腐剤(例えば、ポビドンヨード、塩化メチルベンゼトニウム等)、駆虫薬(例えば、リンデン、アントラリン等)、鎮痛剤(例えば、サリチル酸メチル、サリチル酸、ディクロニン、アロエ等)、局所麻酔薬(例えば、ベンゾカイン、リドカイン、キシロカイン、ブタンベンピクラート等)、抗炎症剤(例えば、デキサメタゾン、ベタメタゾン、プレドニゾン、プレドニゾロン、トリアムシノロン、ヒドロコルチゾン、アルクロメタゾン、アムシノニド、ジフロラゾン等および非ステロイド性抗炎症薬のようなステロイド化合物)、抗疥癬および炎症緩和化合物(例えば、ジフェンヒドラミンのような抗ヒスタミン薬および乾癬治療薬)、火傷鎮静化合物(例えば、o−アミノ−p−トルエンスルホンアミド、モノアセタート等)、脱色剤(例えば、モノベンゾン)、およびホルモン剤(例えば、エストリオール)を含むが、(さらに上記の局所剤に加えて)それらに限定されるわけではない。
【0031】
上に列挙した化合物を含有する本発明に用いることができる化合物は、製薬学的に許容可能な塩類および結合体の全てを含むことを意味する。
他の局所性活性化合物は、レミントンの薬科学、17版、Merck Publishing Co.、Easton、Pa.(1985)、773〜791頁および1054〜1058頁(以下、レミントン)に記載され、ここに参照して組み込まれる。
さらに本発明の医薬製剤は、美容目的、例えば、発汗抑制剤、日焼け止め、表皮剥奪、皮膚軟化剤、芳香剤および抗ざ瘡製剤などの他の用途に用いることができる。
これらの医薬製剤は、p−安息香酸ジメチルアミノのような日焼け止め、尿素のような皮膚軟化剤、サリチル酸のような角質溶解剤、過酸化ベンゾイルのようなざ瘡剤、香料等を含む。
適切な制汗組成物は収斂性塩類を含有する。収斂性塩類は、アルミニウム、ジルコニウム、亜鉛の有機および無機塩類ならびにそれらの混合物を含む。収斂性塩の陰イオンは、例えば、硝酸塩、塩化物、クロロヒドロキシド、ミョウバン、蟻酸塩、乳酸塩、ベンジルスルホネートまたはフェニルスルホネートであってもよい。制汗収斂性塩類の具体例は、ハロゲン化アルミニウム、アルミニウムヒドロキシハライド、ジルコニルオキシハライド、ジルコニルヒドロキシハライドおよびそれらの混合物を含む。
【0032】
具体的なアルミニウム塩類は、塩化アルミニウムおよびアルミニウムヒドロキシハライドを含む。具体的なジルコニウム化合物は、ジルコニウムオキシ塩類およびジルコニウムヒドロキシ塩類を含み、さらに、ジルコニル塩類およびジルコニルヒドロキシ塩類と呼ばれる。
したがって、具体的な制汗性化合物は、アルミニウムブロモハイドレート、カリウムミョウバン、ナトリウムアルミニウムクロロヒドロキシラクテート、硫酸アルミニウム、アルミニウムクロロハイドレート、アルミニウム−ジルコニウムテトラクロロヒドレート、グリシンと複合したアルミニウム−ジルコニウムポリクロロヒドレート、アルミニウム−ジルコニウムトリクロロヒドレート、アルミニウム−ジルコニウムオクタクロロヒドレート、アルミニウムセスキクロロヒドレート、アルミニウムセスキクロロヒドレクスPG、アルミニウムクロロヒドレクスPEG、アルミニウムジルコニウムオクタクロロヒドレクスグリシン コンプレクス、アルミニウムジルコニウムペンタクロロヒドレクスグリシン コンプレクス、アルミニウムジルコニウムテトラクロロヒドレクスグリシン コンプレクス、アルミニウムジルコニウムトリクロロヒドレクスグリシン コンプレクス、アルミニウムクロロヒドレクスPG、ジルコニウムクロロヒドレート、アルミニウムジクロロヒドレート、アルミニウムジクロロヒドレクスPEG、アルミニウムジクロロヒドレクスPG、アルミニウムセスキクロロヒドレクスPG、塩化アルミニウム、アルミニウムジルコニウムペンタクロロヒドレートおよびそれらの混合物を含むが、それらに限定されるわけではない。他の多数の有用な制汗性化合物は、WO91/19222号およびCosmetic and Toiletry Fragrance Handbook、The Cosmetic, Toiletry and Fragrance Association, Inc,、Washington, D.C.、56頁、1989に記載され(以下、CTFA ハンドブック)、ここに参照して組み込まれる。
【0033】
本発明の第1観点による医薬製剤は、以下により詳しく実質的に記載されるように皮膚投与に適したどのような治療剤と一緒に用いるのに適している。しかし、本発明の第1観点の医薬製剤は、特に、動物の患者に少なくとも1つの局所麻酔薬を皮膚投与するのに適しているため、本発明の第1観点の医薬製剤が、それによって皮膚投与されるべき治療剤として少なくとも1つの局所麻酔薬(特に、リドカインとしても知られているリグノカイン)を含むことが好ましいかもしれない。あるいは、本発明の第1観点の医薬製剤は、特に、動物の患者に少なくとも1つのコルチコステロイドを皮膚投与するのに適しているため、上述される本発明の第1観点の医薬製剤が、それによって皮膚投与されるべき治療剤として少なくとも1つのコルチコステロイド(特に、ヒドロコルチゾン)を含むことが好ましいであろう。
したがって、本発明の第1観点による特に好ましい医薬製剤は、動物の患者にリグノカインを皮膚投与するための医薬製剤を含み、周囲温度で、ウィテップゾールS55を含む担体媒体と混合したリグノカインの単位用量を含む実質的に固形状の剤形を有する。その医薬製剤は、固形状の剤形で特徴付けられ、動物の患者の皮膚面積にそれを塗布する時に軟化し得ることによって、皮膚面積に塗布後、実質的に固形状剤形は、動物の患者にリグノカインの単位用量を実質的に(実質的に完全に)投与するために、皮膚面積で(実質的に完全に)吸収され得る粘稠度に軟化される。
【0034】
本発明の第1観点による特に好ましい代替製剤は、動物の患者にヒドロコルチゾンを皮膚投与するための製剤を含み、周囲温度で、実質的にココア脂からなる担体媒体と混合したヒドロコルチゾンの単位用量を含む実質的に固形状の剤形を有する。その製剤は、実質的に固形状の剤形で特徴付けられ、動物の患者の皮膚面積にそれを塗布した時に軟化し得ることによって、皮膚面積に塗布後、実質的に固形状剤形は、動物の患者にヒドロコルチゾンの単位用量を実質的に(実質的に完全に)投与するために、皮膚面積で(実質的に完全に)吸収され得る粘稠度に軟化される。
なお、本発明の第1観点によるさらに特に好ましい代替製剤は、動物の患者にヒドロコルチゾンを皮膚投与するための製剤を含み、周囲温度で、実質的にウィテップゾールH15からなる担体媒体と混合したヒドロコルチゾンの単位用量を含む実質的に固形状の剤形を有する。その製剤は、実質的に固形状剤形で特徴付けられ、動物の患者にそれを塗布する時に軟化し得ることによって、皮膚面積に塗布後、実質的に固形状剤形は、動物の患者にヒドロコルチゾンの単位用量を実質的に(実質的に完全に)投与するために、皮膚面積で(実質的に完全に)吸収され得る粘稠度に転化される。
【0035】
上述された本発明の第1観点によって、動物の患者の皮膚面積に塗する場合に、医薬製剤を実質的に覆うように配置することができる被覆部材と共に実質的に上述されるような本発明の第1観点の医薬製剤を含む薬品およびその被覆部材を動物の患者の皮膚面積に貼着するための手段がさらに提供される。
好ましくは、本発明の第1観点の製品は、動物の患者の皮膚面積に塗布する場合に、医薬製剤を実質的に覆うのに適した実質的に軟質な基体と共に実質的に上述されるような本発明の第1観点の医薬製剤を含む医薬用経皮パッチの形状で提供される。その基体は、(通常、それに塗布される粘着性被覆剤の形状で)動物の患者の皮膚面積にそれを貼着するための接着手段を有する。パッチは動物の患者の皮膚面積に貼着することができるため、実質的に固形状の剤形の温度がその軟化点以上、皮膚で吸収され得る粘稠度まで上昇するように皮膚と接触させて、製剤の実質的に固形状剤形を保持し、動物の患者に治療剤の単位用量の投与を行う。
本発明の第1観点で提供されるような適切なパッチの基体は、製剤に実質的に浸透しない。適切には、その基体は、従来の硬膏剤への使用に適した種類のポリマーフィルムであってもよい。
【0036】
上述される本発明の第1観点による製品の代替実施形態において、被覆部材が、患者の皮膚に塗布される場合に、使用時に製剤を重ねるために配置されているけれども、製品は、プラスチックフィルム状である必要があり、塗布した製剤と間隔をあけることによって、製剤が塗布された皮膚面積近傍に湿性の限局雰囲気が生じるかもしれない。このように、湿性の限局雰囲気は、患者の皮膚で吸収されるために実質的に固形状の剤形の軟化を助けることができる。
より詳しく以下に実質的に記載されるように、治療剤が皮膚の局所症状の治療用である場合、動物患者の皮膚の少なくとも外部表皮層による実質的な吸収は、患者の治療には十分であり、血流への実質的な経皮的経路が必要であるが、実際は、場合によって望ましくないであろうことが理解できるだろう。
例えば、接着防止剤(例えば、滑石等)から選択してもよい1以上の錠剤化補助物、フロー補助物(例えば、二酸化珪素等)および圧密補助物(例えば、微晶質セルロース、燐酸二カルシウム等)または錠剤化補助物として医薬製剤への使用に適した他のいかなる成分および上述される本発明の第1観点による方法を、実質的に上述されるような本発明の第1観点の医薬製剤、その結果として、本発明のその製造方法に使用することが有利であるかもしれない。
本発明はさらに、より詳しく以下に実質的に記載されるような少なくとも1つの治療剤の単位用量を含有し、動物患者の皮膚面積に塗布する前は、周囲温度で、動物患者の皮膚面積への塗布に適した拡散粘稠度を有する製剤の提供に関することにより、塗布後、製剤は治療剤の単位用量を投与するために吸収されるであろう。
【0037】
したがって、本発明はさらに、以下により詳しく実質的に記載されるような少なくとも1つの治療剤の単位用量を含有し、動物の患者に皮膚投与するための軟膏またはクリームの提供に関する。
したがって、本発明の第2観点によれば、動物の患者の皮膚面積に塗布する前に、周囲温度で、動物患者の皮膚面積への塗布に適した拡散粘稠度を有する製剤(つまり、通常、周囲温度で軟膏およびクリーム状の製剤)の製造方法が提供され、その方法は、本発明の第1観点による方法に関して実質的に上述されるように、少なくとも1つの治療剤およびその担体媒体の混合物を製造し、成形した後、混合物が拡散粘稠度を有する温度に到達させることから構成される(この温度は、ここで、本発明の製剤の拡散点と称し、以下により詳しく記載する)。
通常、本発明の第2観点の方法では、実質的に上述されるような混合物の少なくとも一部を成形する間、周囲温度以下の温度および通常、約15℃以下、有利には約10℃以下、例えば、約0℃以下の温度で拡散粘稠度に実質的に転化される実質的に固形状のものが製造される。
【0038】
本発明の第2観点による方法では、実質的に固形状のものは、医薬製剤の拡散点未満の温度および通常、約15℃以下、有利には約10℃以下、例えば、約0℃以下の温度で成形することによって製造されることが一般的に好ましい。
本発明の第2観点の特定の実施形態によれば、動物患者への皮膚投与に適した少なくとも1つの治療剤の単位用量を含有し、動物の患者の皮膚面積に塗布する前に、周囲温度で、動物患者の皮膚面積への塗布に適した拡散粘稠度を有する医薬製剤の製造方法が提供される。その方法は、以下から構成される:
(a)少なくとも1つの治療剤とそのための少なくとも1つの担体媒体を混合して、それらの混合物を得、
(b)約15℃以下の温度で、ステップ(a)で得られた混合物の少なくとも一部を成形する。
成形のステップは、有利には、約10℃以下、例えば、実質的に上述されるような約0℃以下の温度で行われる。有利には、ステップ(b)で得られるように成形された部分は、より詳しく以下に実質的に記載されるように、例えば、そのための個々の密閉型容器に包装され、続いて、包装された部分は、適切には、周囲温度に実質的に温めることが可能である。
したがって、好ましくは、本発明の第2観点の方法は、さらに、実質的に固形状のものをその拡散点に実質的に温めさせる前に(つまり、実質的に固形状のものが拡散粘稠度に転化される温度に達する前に)、実質的に上述されるように製造された実質的に固形状のものを包装するステップを含む。このように、より詳しく以下に実質的に記載されるような包装用量、より詳しくは製剤の実質的に別々の複数の包装用量を本発明の第2観点により提供することができる。クリームまたは軟膏状の本発明の第2観点による医薬製剤のそのような包装用量または別々の包装用量は、患者または付添い医師により扱い易く、塗布しやすいのと同時に、それによって投与されるべき1以上の治療剤の比較的正確な投与がさらに可能である。
【0039】
本発明の第2観点による特に好ましい工程は、順序が特定されている以下から構成される:
(a)動物の患者への皮膚投与に適した少なくとも1つの治療剤およびその担体媒体を混合して、それらの混合物を得、
(b)ステップ(a)で得られた混合物を(好ましくは約10℃以下、好ましくは約0℃以下の温度で)冷却して、それを実質的に凝固させ、
(c)ステップ(b)で得られた実質的に凝固した混合物の少なくとも一部を成形し(通常、約15℃以下の温度、有利には約10℃以下、例えば、約0℃以下の温度で)、実質的に固形状のものを提供し、
(d)その結果、ステップ(c)で得られた実質的に固形状のものを周囲温度に到達させて、拡散粘稠度に転化する。
ここに実質的に記載されるように、本発明で提供されるような医薬製剤が、以下により詳しく実質的に記載されるように防腐剤が実質的に存在しないことが好ましいであろう。そのような場合、本発明の方法は無菌状態下で行われることが好ましい。
【0040】
さらに実質的にここに記載されるように、本発明で提供されるような医薬製剤が、より詳しく以下に実質的に記載されるように酸化防止剤が実質的に存在しないことが好ましいかもしれない。そのような場合、本発明の方法が医薬製剤の包装を含む場合、そのような包装は窒素等のような実質的に不活性雰囲気中で行われることが好ましい。
本発明の第2観点によれば、動物の患者への皮膚投与に適した少なくとも1つの治療剤の単位用量を含有し、動物患者の皮膚面積に塗布する前に、周囲温度で、動物患者の皮膚面積への塗布に適した拡散粘稠度を有する医薬製剤がさらに提供される。
さらに詳しくは、動物患者への皮膚投与に適した少なくとも1つの治療剤の単位用量およびその担体媒体の大部分からなる軟膏またはクリームも提供され、その軟膏またはクリームは、周囲温度以下の拡散点を有する。
さらに、本発明の第2観点による医薬製剤の複数の別個用量からなり、各用量が、動物患者の皮膚温度以下の温度で拡散粘稠度を有し、さらに詳しくは、通常、周囲温度の拡散粘稠度、より一般的には、約15℃以下、例えば、約10℃以下の温度で拡散粘稠度を有する薬剤が提供される。
【0041】
本発明の第2観点の特に好ましい実施形態によれば、動物患者への皮膚投与に適した少なくとも1つの治療剤の皮膚投与用の医薬製剤が提供され、その薬剤は、それぞれが少なくとも1つの治療剤を含有する複数の別個用量からなり、各剤形は以下:
少なくとも1つの治療剤の単位用量および
動物患者の皮膚面積に塗布する前に、周囲温度で、皮膚面積への塗布に適した拡散粘稠度を有する担体媒体
を含む混合物からなる。
それによって、動物患者の皮膚面積への塗布後、用量は、動物患者の皮膚面積で実質的に(実質的に完全に)吸収することができ、動物患者に治療剤の単位用量を実質的に(実質的に完全に)投与される。
好ましくは、本発明の第2観点による医薬製剤に使用されるような担体媒体、より詳しくは、本発明の第2観点による医薬製剤は、約15℃以下の拡散点を有するかもしれない。有利には、本発明の第2観点の医薬製剤に用いられるような担体媒体、より詳しくは、本発明の第2観点による医薬製剤は、約10℃以下、例えば、約0℃以下の拡散点を有するかもしれない。したがって、本発明の第2観点によるそのような医薬製剤は、周囲温度以下の拡散点を有するかもしれない。拡散点が周囲温度以下の場合、医薬製剤が、周囲温度で貯蔵または塗布される時は固形状ではないであろうことが理解できるだろう。一般的に、そのような医薬製剤は、実質的に上述されるような拡散点以下の温度で実質的に固形製剤として製造されるであろうが、実質的に上述されるように再度充填後、拡散点を越える温度に温めてもよい。
【0042】
好ましくは、担体媒体は、本発明の第2観点の医薬製剤の重量に基づいて、約60重量%以上、より好ましくは約80重量%以上およびより一層好ましくは約90重量%を構成する。
本発明の第2観点による医薬製剤に使用するための担体媒体は、実質的に上述されるような皮膚使用に許容され得る適切ないかなる物質であってもよい。皮膚温度でクリーム状であるべき製剤の場合、担体媒体は乳濁液を含んでもよい。皮膚温度で軟膏状であるべき製剤の場合は、担体媒体は油を含んでもよい。
本発明の医薬製剤への使用に適した担体媒体は、坐薬(例えば、飽和脂肪酸の1以上のグリセロールエステルまたは1以上のポリグリコール化グリセリドのような1以上のグリセリド、カカオ脂、シイオブローマ等を含有する)、1以上の高分子量ポリエチレングリコール、1以上のポリオキシエチレン、ラノリンおよびそれらの誘導体、1以上の脂肪酸、脂肪アルコール、脂肪酸エステル(例えば、カプリル酸、トリカプリルグリセリル等を含有する)および1以上の有機油(例えば、硬化植物油を含有する)等への使用に適した種類の成分からなる群から選択されるかもしれない。
本発明の第2観点による医薬製剤に使用するのに特に適した担体媒体は、実質的に、カカオ脂および例えば、ヒマシ油または扁桃油のような少なくとも1つの有機油のような完全な混合物からなる。
本発明は、ここに記載されるような動物患者への皮膚投与に適した少なくとも1つの治療剤の単位用量を動物患者に投与するために、実質的に上述されるような製剤を動物患者に皮膚投与することで動物の患者を治療する方法をさらに提供する。
【0043】
さらに詳しくは、本発明は、動物患者に少なくとも1つの治療剤を皮膚投与する方法を提供し、その治療剤は、実質的に上述されるように本発明の第1観点の医薬製剤によって提供され、その投与方法は、以下から構成される:
実質的に上述されるように本発明の第1観点による医薬製剤の実質的に固形状の剤形を動物患者の皮膚面積に塗布し、
実質的に固形状の剤形を動物患者の皮膚面積で(実質的に完全に)吸収され得る粘稠度に軟化させるために、動物患者の皮膚面積に接触する塗布された医薬製剤を維持し、
それによって、治療剤の単位用量を動物患者に(実質的に完全に)投与する。
さらに本発明は、動物患者に少なくとも1つの治療剤を皮膚投与する方法を提供し、その治療剤は、実質的に上述されるような本発明の第2観点による医薬製剤で提供され、その方法は、以下から構成される:
実質的に上述されるような本発明の第2観点の医薬製剤を動物患者の皮膚面積に塗布し(通常、実質的に上述されるような本発明の第2観点の医薬品から動物患者への皮膚投与に適した少なくとも1つの治療剤を施すことによって)、
実質的に上述されるような本発明の第2観点の塗布した製剤(または少なくとも1つの施された別個の用量)を動物患者の皮膚面積に実質的にすりこむことによって、実質的に上述されるような本発明の第2観点による塗布した製剤(または少なくとも1つの施された別個の用量)は皮膚で(実質的に完全に)吸収することができ、
それによって、治療剤の単位用量を動物の患者に(実質的に完全に)投与する。
【0044】
本発明により、動物患者への皮膚投与用の薬物の製造に使用するために、実質的に上述されるような医薬製剤がさらに提供され、製剤またはここの実施例のいずれか1つに実質的に記載されるような医薬品もさらに提供される。
ここで用いられるような用語「治療剤」は、動物患者(特に人間)への皮膚投与に適し、(本発明の第1または第2観点のいずれかで)本発明のどんな医薬製剤または製品への使用にも適したいかなる活性物質を意味し、動物(特に人間)の体に所望の薬理学的治療効果を及ぼすように、上述されるようにそういうものとして皮膚投与することができるいかなる活性物質を通常含んでいてもよい。ここで用いられるような用語「治療剤」は、例えば、製薬学的に許容可能な塩、エステル、プロドラッグまたはそれらの代謝産物のような製薬学的に許容可能なそれらと同等のいかなるものをさらに含む。開示された薬剤の全ての異性体もこの開示により含まれる。
ここで用いられるような用語「皮膚投与する」または「皮膚投与」は、(i)以下により詳しく実質的に記載されるように皮膚疾患の局部または局所的治療のために本発明への使用に適した治療剤の投与および(ii)非局所治療のため、つまり、より詳しく以下に実質的に記載されるような全身療法のための動物(特に人間)の患者の血流への投与のために本発明への使用に適した治療剤の投与を含む。
【0045】
ここで用いられる用語「治療」は、慢性状態の治療およびその予防を意味する。本発明によるいかなる医薬製剤、医薬品または方法についての正確な治療状態は、当然治療されるべき症状の正確な性質、動物(特に人間)の患者の年齢および性別次第であり、結局、付き添い医師の判断にまかされるであろう。
上述したように、本発明に従って用いるための治療剤は、局部活性(多くの場合これが好ましい)または非局部活性を有するかもしれない。
本発明のいかなる観点に従って用いるための局部活性を有する治療剤は、例えば、皮膚疾患の治療に使用する作用物質を含む。一例として、そのような疾患は、乾癬、湿疹、ざ瘡、おむつかぶれおよび他の皮膚の炎症性疾患、皮膚の細菌感染または真菌感染、皮膚の悪性疾患、疣贅等を含む。
有利には、本発明に従って用いるための局部活性を有する治療剤は、局所麻酔薬、コルチコステロイド、抗菌剤、抗黴剤またはそれらの治療学上効果的ないかなる組み合わせからなる群から選択することができる。
より詳しくは、本発明に従って用いるための局部活性を有する治療剤は、テトラカイン、ベンゾカイン、リグノカイン、ヒドロコルチゾン、ベクロメタゾン、ジプロプリオネート、プロピオン酸クロベタゾール、プロピオン酸フルチカゾン、イクタモール、コハク酸リチウム、コールタール、ジトラノール、過酸化ベンゾイル、トレチノイン、硫黄、ビタミンDおよびそれらの誘導体、フラマイセチン、塩酸クロルテトラサイクリン、フシジン酸、クロトリマゾール、エコナゾール、アモロルフィンおよびターベナファインまたはそれらの治療学上効果的ないかなる組み合わせからなる群から選択することができる。
本発明は、以下により詳しく実質的に記載されるようにリグノカインまたはヒドロコルチゾンの局部への送達を行うのに特に適している。
【0046】
本発明のいかなる観点に従って用いるための非局部活性を有する治療剤は、例えば、様々な全身性疾患およびそれらの症状、例えば、心臓血管系疾患、筋肉または関節の異常、臓器の疾患の治療または予防に用いる作用物質を含む。より詳しくは、本発明のいかなる観点によって用いるための非局部活性を有する治療剤は、例えば、血管拡張薬として使用する作用物質、動揺病の治療用作用物質、避妊薬、ホルモン補充剤、鎮痛剤および禁煙補助物またはそれらの治療学上効果的ないかなる組み合わせを含む。
本発明のいかなる観点に従って用いるための非局部活性を有する治療剤は、有利には、ニトログリセリン、スコポラミン、エストラジオール、ノルエチステロン、フェンタニールおよびニコチンまたはそれらの治療学上効果的ないかなる組み合わせからなる群から選択される。
本発明に使用される治療剤は、治療学上効果的な濃度、例えば、医薬製剤の全重量に基づいて少なくとも0.01重量%で存在すべきである。一般的に、治療剤は、医薬製剤の全重量に基づいて10重量%以下、有利には2重量%以下、より有利には5重量%以下、好ましくは1重量%以下、より好ましくは0.05重量%以下の量で存在するであろう。
適切には、本発明の医薬製剤は、適切であれば、例えば、1以上の硬化剤、1以上の可塑剤等の付加成分をさらに含んでいてもよい。適切な硬化剤は、例えば、蜜蝋、セチルアルコール、ステアリン酸、ステアリルアルコール、モノステアリン酸アルミニウム、ベントナイト等を含む。適切な可塑剤は、例えば、モノステアリン酸グリセリル、ミニスチルアルコール、ポリソルベート80、プロピレングリコール等を含む。
適切には、本発明の医薬製剤は、適切であれば、例えば、治療剤用の1以上の浸透向上剤(界面活性剤、アルコール、エステル、グリコール等または他の適したいかなる浸透相乗剤であってもよい)、湿潤剤、(陽イオン、非イオン、陰イオンまたは高分子であってもよい)界面活性剤、乳化剤、酸化防止剤、防腐剤、粘土、泡消し剤、展着剤、皮膚軟化薬、バリア、可溶化剤等のような付加成分をさらに含んでいてもよい。
【0047】
しかし、本発明の特定の観点において、通常、本発明の医薬製剤は一般的に皮膚投与のための医薬製剤に含まれる種類の防腐剤が実質的に存在しないことが好ましく、または皮膚投与のための製剤に通常必要な量以下のそのような防腐剤を少なくとも含んでいてもよく、もしくは以下に実質的に記載されるように病気にかかりやすい患者に実質的なアレルギー性反応を一般的に引き起こさない量の防腐剤のようなものを少なくとも含むであろうことが好ましい。一般的に皮膚投与のための製剤に使用されるそのような防腐剤は、そのような製剤が繰り返し取り扱われるので、そのような皮膚用製剤の汚染を予防するために存在し、本発明で得ることができる皮膚上の単位用量により、本発明で必要ではないかもしれない。実際は、度々の取扱により汚染を未然に防ぐためのそのような防腐剤の使用は、患者によっては、病気にかかりやすい患者にアレルギー性反応を引き起こすので有害であり、本発明は、病気にかかりやすい患者のそのようなアレルギー性反応を防ぐので有益であるかもしれない。アレルギー性反応と関連した防腐剤は、クロロクレゾール、ヒドロキシベンゾエート(パラベン)、ポリソルベート、ソルビン酸等を含み、例えば、以下の登録商標、ドラポレン(Drapolene)、メディカイド(Medicaid)、シオペル(Siopel)、スプリオン(Sprilon)、オーラックス(Eurax)、エフコルテラン(Efcortelan)、マイルディソン(Mildison)、フシジンH(Fucidin H)、ニスタフォーム(Nystafrom)、キノコート(Quinocort)、テラ−コートリル(Terra−Cortril)、ナイスタチン(Nystatin)、チモジン(Timodine)、ロコイド(Locoid)、ロコイドクレロ(Locoid Crelo)、モドラソン(Modrasone)、プロパデルム(Propaderm)、ベトノベート(Betnovate)、ベトノメートRD(Betnovate RD)、ジプロソン(Diprosone)、デルモベート(Dermovate)、オイモベート(Eumovate)、トリモベート(Trimovate)、ネリソン(Nerisone)、ハーラン(Haelan)、シナラル(Synalar)、ウルトララナムプライン(Ultralanum Plain)、ゾラック(Zorac)、カルボ−ドーム(Carbo−Dome)、エクソレックス(Exorex)、ジフェリン(Differin)、エクセルデルム(Exelderm)等のいずれかで入手可能な製剤を含む先行技術の多くの局所製剤に存在することが公知である。
【0048】
しかし、本発明の医薬製剤は、製造中、本発明の医薬製剤の汚染を実質的に防ぐために通常含まれるフェノキシエタノール等のような1以上の防腐剤をさらに含むが、上述されるように手使用のため、一般的に、感染を防ぐために使用される種類のものではない。
さらに本発明の医薬製剤は、皮膚投与用の製剤に一般的に含有される種類の酸化防腐剤が実質的に存在しないであろうことが好ましく、または皮膚投与のための製剤に通常必要な量以下のそのような酸化防腐剤を少なくとも含んでいてもよく、もしくは以下に実質的に記載されるように病気にかかりやすい患者に実質的なアレルギー性反応を一般的に引き起こさない量の酸化防腐剤のようなものを少なくとも含むであろうことが好ましいかもしれない。一般的に皮膚投与のための製剤に使用されるそのような酸化防腐剤は、そのような酸敗性の製剤に存在する脂肪を防ぐために一般的に存在し、一般的な保管に有効で、使用において主に開封後の酸化を防ぐために存在するであろう。そのような酸化防腐剤は、本発明で得ることができる皮膚上の単位用量により、本発明で必要ではないかもしれないし、または先行技術の製剤で使用されるより少ない程度に、少なくとも必要であり、もしくはより詳しくは、病気にかかりやすい患者に実質的なアレルギー性反応を通常引き起こさない濃度で使用されるかもしれない。そのような酸化防止剤の使用は、患者によっては、病気にかかりやすい患者にアレルギー性反応を引き起こすので有害であり、本発明は、病気にかかりやすい患者のそのようなアレルギー性反応を未然に防ぐので有益であるかもしれない。アレルギー性反応と関連した酸化防止剤は、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン等を含み、例えば、登録商標イムダーム(Imuderm)、シオペル(Siopel)等のいずれかで入手可能なこれらの製剤等の先行技術の局所製剤で入手できることが公知である。
【0049】
ここで用いられるような用語「軟化点」は、医薬製剤中の治療剤の単位用量を患者に投与するために、上述されるように、本発明の第1観点による医薬製剤に使用されるような実質的に固形状の剤形が、患者の皮膚で吸収され得る粘稠度に軟化し始める温度のことを言う。
実質的に上述されるような本発明の第1観点による医薬製剤の実質的に固形状の剤形の「軟化点」は、実質的に固形状の剤形が患者の皮膚で吸収され得る粘稠度に軟化し始める温度として可視的に測定することができ、それ自体は、有利には、患者の皮膚上に望ましくない残渣を実質的に残さないように、患者の皮膚で実質的に完全に吸収され得る。
有利には、実質的に上述されるような本発明の第1観点による医薬製剤の実質的に固形状の剤形の「軟化点」は、適切には5kgの重量計を備えるTA−XT2質感分析器を用いて測定することができる。装置を(−60℃〜200℃の範囲で操作可能な)温度調節チャンバーに入れる。本発明の錠剤または他の実質的に固形状の剤形は、特定温度で少なくとも10分間チャンバーに入れていてもよい。3mmの平面プローブを、1mmの間隔で、0.1mm/秒の速度で本発明の錠剤または他の実質的に固形状剤形に押入れる。
増加温度1℃で測定を繰り返すことができ、(Texture Exceed softwareで測定されるような)記録済の最大抵抗力が本発明の「固形状」錠剤または他の実質的に固形状剤形の抵抗力の50%以下に下降する温度で、錠剤または他の剤形は「軟化する」と考えられる。
【0050】
本発明の第1または第2観点のいずれかによる医薬製剤に関するここで用いられるような用語「拡散点」は、例えば、製剤そのものの重量で流れ出るかもしれないし、または例えば、指圧を用いて動物患者の皮膚上に少なくとも薄く塗ることができる製剤が「拡散」粘稠度を有する温度のことを言う。拡散粘稠度を有する製剤の流動性は、皮膚に向かって治療剤を移動させて、例えば、拡散によって皮膚への治療剤の吸収を促進するであろう。製剤の拡散点は、軟化点の測定に関して上述されるTA−XT2質感分析器を用いて測定してもよく、製剤の拡散点は、この分析器を用いて、平面プローブが調製剤中に入れられる前に製剤の外部流出が最初に観察される温度である。
用語「単位用量」は、例えば、治療上の活性剤または美容薬剤のような投与すべき薬剤の有効量を含有する単回投与に適した製剤を意味する。
本発明の医薬製剤は、いわゆるブリスターパックに包装することができる。ブリスターパックは、包装産業でよく知られており、製薬学的な単位剤形の包装に広く用いられている。一般的に、ブリスターパックは、好ましくは透明なプラスチック材のホイルで覆われた比較的硬質素材のシートからなる。包装工程中、陥凹がプラスチックホイルに形成される。陥凹は、包装されるべき製剤の大きさおよび形状を有する。本発明の医薬製剤を陥凹に入れることができ、比較的硬質素材のシートを、陥凹が形成された方向と逆のホイル面のプラスチックホイルに対して密閉する。その結果、製剤はプラスチックホイルおよびシートの間の陥凹で密閉される。好ましくは、シートの強度は、製剤を陥凹に手で加圧してブリスターパックから取り出すことができるような強度であることにより、開口部が、製剤全体に影響を及ぼすことなく、陥凹の場所のシートに形成される。他の実施形態では、ホイルは剥がすことができる。したがって、本発明の製剤は開口部を介して取り出すことができる。
【0051】
例えば、そのように特定された製剤を塗布すべき規制日数と一致する数の形で、ブリスターパック上に記憶補助物を備えることが望ましいかもしれない。そのような記憶補助物の別の例は、以下のような例えば、「第1週、月曜日、火曜日等、第2週目、月曜日、火曜日」等のようなカード上に印刷されたカレンダーである。他の様々な記憶補助物は、容易に理解できるであろう。「1日量」は、所定日に塗布すべき1つの製剤またはいくつかの製剤であり得る。
本発明の医薬製剤は、最終の製造工程および包装中、好ましくは投与時に固形状であることが好ましい。
現在、本発明は以下の実施例でさらに例証されるであろうが、決して本発明を限定するものではない。
【0052】
実施例1
錠剤成分:
リグノカイン 2%
トウィーン62(乳化剤) 5%
ウィテップゾール S55* 93%
*低溶解(33〜35℃)トリグリセリド。
百分率比は、組み合わせた成分の全重量に基づいた重量である。
製造方法:
1. 成分を高せん断ミキサー配合機中で5分間混合し、顆粒状混合物を形成する。混合物を容器に含まれるドライアイスに浸漬して冷却した。
2. 錠剤を10mmの平面ジルコニア工具を用いてManesty F 圧縮機で圧縮した。混合物を圧縮下で凝縮し、次いで、凝固して錠剤を形成した。
【0053】
実施例2
錠剤成分:
ヒドロコルチゾン 0.005g
カカオ脂 0.275g
製造方法:
カカオ脂を、均一に溶けるまで徐々に溶解した。次いで、ヒドロコルチゾンを添加し、徐々に加熱しながら混合した。混合物を冷却し、次いで、冷蔵庫で一晩放置して硬化させた。一旦硬化し、次いで、固形物を砕いて粒状化した。
錠剤を、10mm平面のステンレス製スチール/ジルコニア工具を用いてTA−XT2で圧縮した。混合物を圧縮下で凝縮し、次いで凝固して錠剤を形成した。
【0054】
実施例3
錠剤成分:
ヒドロコルチゾン 0.005g
ウィテップゾール H15 0.334g
製造方法:
ウィテップゾール H15を均一に溶けるまで徐々に溶解した。次いで、ヒドロコルチゾンを添加し、徐々に加熱しながら混合した。混合物を冷却し、次いで、冷蔵庫で一晩放置して硬化させた。一旦硬化し、次いで、固形物を砕いて粒状化した。
錠剤を、10mm平面のステンレス製スチール/ジルコニア工具を用いてTA−XT2で圧縮した。混合物を圧縮下で凝縮し、次いで、凝固して錠剤を形成した。
【0055】
実施例4
投与量の成分
ヒドロコルチゾン
担体
4つの異なる担体製剤を、以下のように実施例4に従って製造された投与量で使用した。
製剤1:
50%ヒマシ油
50%カカオ脂
製剤2:
60%ヒマシ油
40%カカオ脂
製剤3:
70%ヒマシ油
30%カカオ脂
製剤4:
70%扁桃油
30%カカオ脂
【0056】
製造方法
製剤1〜4に記載されるようなカカオ脂および選択された油を均一に溶けるまで徐々に溶解した。次いで、ヒドロコルチゾンを添加し、徐々に加熱しながら混合した。混合物を冷却し、次いで、冷蔵庫で放置して硬化させた。一旦硬化し、固形物を砕いて、次いで低温で粒状化した。
投与量は、10mm平面のステンレス製スチール/ジルコニア工具を用いてTA−XT2で圧縮することによって調製された。混合物を圧縮下0〜−4℃の温度で凝縮および凝固して、室温に到達させ、実質的に軟化した固形投与量を形成した。[0001]
The present invention relates to pharmaceutical formulations for the dermal administration of therapeutic agents to animal patients, pharmaceuticals containing them, and therapeutic methods using such pharmaceuticals and pharmaceuticals.
In treating local diseases such as skin infections, it is often desirable to formulate therapeutic agents in a form that has a local or local effect. Topical formulations are available in various forms, including creams, ointments, solutions, lotions, suspensions, pastas, emulsions, foams, and the like. Water-miscible creams are generally used for wet or exudative injuries, while ointments are generally used for dry, mushy or scale-like injuries or when more occlusive effects are required. Selected. Lotions are generally effective when minimal application to large or hairy areas is needed or for the treatment of exudative damage.
In any dosing regimen, accurate dosing is important, and in the case of topical preparations substantially as described above, it is particularly important that the patient carefully follow the instructions to avoid side effects. For example, it is generally difficult to know the exact amount of formulation required for use, and such a topical formulation may accidentally reach a higher dose than the recommended dose.
Appropriate amounts of topical formulations conventionally prescribed for a particular part of the body are as follows:
[0002]
[Table 1]
[0003]
The above amounts are generally suitable for an adult twice daily application for a week. However, the above recommendations are not applicable to all topical formulations, and many types of topical formulations require specialized dosing regimens. For example, the above recommendations do not apply to corticosteroid preparations. More particularly, for potent corticosteroid preparations, absorption of the cutaneous pathway may cause severe pituitary-adrenal depression and Cushing's syndrome, both of which are dependent on the area of the body being treated and the duration of the treatment. Therefore, great care must be taken when applying. Therefore, corticosteroid preparations are usually applied once or twice a day (there is no need to apply them frequently), and the appropriate amounts conventionally prescribed for specific parts of the body are: is there:
[0004]
[Table 2]
[0005]
In addition, treatment of severe atopic eczema of the limbs or body (or the development of mild to moderate eczema) often still requires additional attention. For example, treatment may require the application of a potent or moderately effective corticosteroid, possibly for the first 1-2 weeks, and then into a weaker formulation as the condition improves. Emollients are also used.
It should be appreciated from the above that the following dosage regimens of topical preparations require careful attention and that special considerations to be taken into account during the course of treatment are those that are acceptable for any therapeutic agent. I can do it. For example, the following are specific examples of prior art topical formulations in which a particular dosing regimen is indicated, especially in extreme amounts. An example is:
-Doxepin hydrochloride, usually recommended to be applied thinly 3-4 times a day, with a maximum dose of 3 g per application, with a maximum dose of 12 g per day, a suitable coverage is approx. Should be less than 10%,
-Clobetasol propionate, usually recommended to be applied 1-2 times a day for up to 4 weeks, with a maximum dose of about 50 g of a 0.05% formulation per week,
Diflucortron valerate, usually at a maximum dose of about 60 g of a 0.3% formulation per week, for up to 4 weeks (0.1% formulation) or 2 weeks (0.3% formulation) per day It is recommended to apply 1-2 times.
[0006]
In particular, the fact that extreme amounts should be monitored has proven to be particularly important for topical formulations of Calcipotriol. For example, it has been found that when the recommended weekly maximum of calcipotriol is exceeded, there is a risk of hypercalcemia. Unfortunately, the above is not always clearly explained in the information of the patient to whom the topical formulation of calcipotriol is provided. Despite the possibility of said hypercalcemia, for example, the topical formulation of calcipotriol, available under the trademark Dovonex®, recommends free application and, as can be understood, That is problematic. However, the recommended dosing regimen for topical formulations of calcipotriol should be applied once or twice daily, with a weekly maximum of 100 g. For patients aged 6 years and older, the formulation should be applied twice a day; for patients aged 6-12 years, the weekly maximum should be 50 g; for patients 12 years and older, the weekly maximum should be 75 g. It is.
[0007]
Providing a means for administering skin treatments to patients in a substantially accurate manner to solve the problems faced by treatment regimens where it is important to monitor extreme amounts of the therapeutic agents for skin administration What you can do is beneficial. Such precise dosing should avoid the previously observed harmful side effects when limits are exceeded.
In the past, the difficulties encountered when attempting to provide accurate dosing described above arise when the therapeutic agent is administered to the skin in a topical formulation, and the ability to measure the exact amount of such topical formulation. Is a problem for the patient. Therefore, it is particularly difficult to ascertain whether a patient has received the correct dose of a therapeutic agent. One method of metering or administering the amount of therapeutic agent applied to a patient's skin with such a topical formulation is that the patient squeezes such a topical formulation from a dispenser, such as a tube, from the index fingertip to the first joint. It is to put out. The amount of therapeutic agent to be so administered is known as a fingertip unit (FTU). Generally, 1 FTU is close to about 500 mg of a topical formulation and is generally sufficient to cover twice the area of an adult palm. However, such administration has not been able to obtain an accurate dose. In particular, what has been described above is problematic in that the FTU is the only appropriate unit, the amount of which varies from patient to patient.
[0008]
Further, it is known to administer a therapeutic agent transdermally by applying an adhesive patch containing the therapeutic agent to the skin of a patient. Such patches typically further include a speed-relieving membrane, an adhesive, a backing and a backing. Adhesives require special formulations to ensure compatibility with other components of such patches, and such formulations often increase the cost of the patch. In addition, because not all therapeutic agents are suitable for inclusion in such patches (usually therapeutic agents having a local therapeutic effect have not previously been used in such patches) Use did not provide a route through which such therapeutic agents could be administered dermally.
Such patches are also called "medicine plasters" in the pharmaceutical field. For example, U.S. Pat. No. 4,765,986 describes a pharmaceutical plaster consisting of a drug present in a carrier substance, which is applied to a porous, flexible synthetic material.
[0009]
Further, U.S. Pat. No. 5,863,941 relates to the dermal administration of a therapeutic agent, and specifically describes a method for treating pathological conditions of the inner ear. More specifically, U.S. Pat. No. 5,863,941 describes the use of a carrier substance and a therapeutic agent, the latter comprising a local anesthetic present in an amount of about 0.5 to 40% by weight of the carrier substance. Carrier materials and therapeutic agents described in US Pat. No. 5,863,941 for use in inner ear therapy may take the form described in US Pat. No. 4,765,986.
For dermal administration of therapeutic agents suitable for delivery in liquid form, EP 0 375 763 B describes an applicator for administering a liquid, such as a pharmaceutical solution, to the skin of a patient. The device described in EP 0 375 763 B comprises a micrometric screw dosing mechanism whose internal cavity can be deformed. However, applicators of the type described in EP 0 375 763 B are, of course, only suitable for the use of therapeutic agents which can be supplied in solution.
The present invention is an improvement over the prior art, which is a pharmaceutical formulation suitable for dermal administration of one or more therapeutic agents to an animal patient, a medicament containing it, a method for producing such a pharmaceutical formulation and medicament, and Methods for treating animal patients using such pharmaceutical preparations and medicaments are provided. In particular, the present invention provides pharmaceutical formulations, pharmaceuticals containing them, methods of making and treating such pharmaceuticals and pharmaceuticals, each of which precisely administers one or more therapeutic agents to the skin of an animal patient. be able to.
[0010]
In certain embodiments, the present invention relates to a pharmaceutical formulation for topical administration to a mammal, comprising a therapeutically effective amount of a unit dose of a therapeutic agent and a pharmaceutically acceptable carrier vehicle thereof, wherein the pharmaceutical formulation comprises: It is a solid at room temperature, has a softening point of 35 ° C. or less, and when placed in continuous contact with the skin of a mammalian patient, provides a unit dose of the therapeutic agent within less than 10 minutes Softens to a consistency that results in substantial application to the desired skin area of the patient.
One embodiment of the present invention is directed to a pharmaceutical formulation for topical administration to a mammal comprising a therapeutically effective amount of a unit dose of the therapeutic agent and a pharmaceutically acceptable carrier vehicle thereof, wherein the pharmaceutical formulation comprises It has a softening point below the skin temperature of the animal patient and has an aspect ratio lower than 1: 1 (wall: surface).
Certain embodiments relate to a pharmaceutical formulation for topical administration to a mammal comprising a therapeutically effective amount of a unit dose of the therapeutic agent and a pharmaceutically acceptable carrier vehicle thereof, wherein the formulation is administered to a mammalian patient. When in continuous contact with the skin, the unit dose of the therapeutic agent softens to a consistency that results in substantial application to the desired skin area of the mammalian patient in less than 10 minutes.
One embodiment relates to a pharmaceutical formulation for topical administration to a mammal, comprising a unit dose of the shaped granules of a therapeutic agent and a pharmaceutically acceptable carrier vehicle thereof, wherein the shaped granules are administered to a mammalian patient. It has a softening point below the skin temperature.
In certain embodiments, the formulation is shaped to facilitate topical administration of the drug. For example, the formulation may have at least one flat surface, at least one concave surface, at least one convex surface, two flat surfaces, two concave surfaces or two convex surfaces. The formulation may be in the form of a standard tablet, sphere or hemisphere. Bullet and conical formulations are not preferred for the present invention.
[0011]
In a preferred embodiment, the formulations of the present invention have a total weight of about 50 mg to less than 1 g, preferably about 100 to 900 mg, more preferably about 250 to 750 mg. Formulations of the present invention may be heavier than 1 g, if desired.
In a preferred pharmaceutical formulation for human patients, the dosage form has a softening point below normal human external temperature (skin temperature). This temperature is usually below about 35 ° C. In certain embodiments, the pharmaceutical formulation has a softening point of about 30-350C or less.
Certain embodiments relate to a pharmaceutical formulation containing a unit dose of at least one therapeutic agent suitable for topical administration to a mammalian patient, wherein the pharmaceutical formulation becomes solid during final manufacture and forms the skin of the mammalian patient. Prior to application to an area, it has a diffusion consistency suitable for application to the skin area, and the pharmaceutical formulation is individually packaged in a plastic container with removable or disintegrable contents to dispense a unit dose. Will be accommodated.
In certain embodiments, the dosage form can be a plurality of substantially discrete, substantially solid particles of a therapeutic agent mixed with a pharmaceutically acceptable carrier medium, wherein the particles are , About 30-35 ° C. The particles can be enclosed in a sachet, capsule, or container suitable for dispensing a unit dose of the particles.
[0012]
In certain embodiments, the present invention is directed to a method of making a pharmaceutical formulation containing a unit dose of at least one therapeutic agent for dermal administration to an animal patient. The method consists of:
(A) mixing at least one therapeutic agent with its carrier medium to obtain a mixture thereof; (b) shaping at least a portion of the mixture obtained in step (a), forming a 1: 1 (wall: surface) A) obtaining a solid formulation having a lower aspect ratio, the resulting formulation having a softening point below the skin temperature of a mammal and, when left in continuous contact with the skin of a mammalian patient, Within a time of less than 10 minutes, the unit dose of the therapeutic agent softens to a consistency that is substantially applied to the desired skin area of the mammalian patient.
[0013]
Other embodiments lead to methods of producing a pharmaceutical formulation effective for topically administering at least one therapeutic agent suitable for topical administration to a mammalian patient. The pharmaceutical formulation contains a unit dose of the therapeutic agent, has a substantially solid dosage form at ambient temperature, and administers the medicament to the skin area of the mammalian patient in order to administer the unit dose of the therapeutic agent to the mammalian patient. It can soften to a consistency that can be absorbed by the skin area when the formulation is applied. The method consists of the following steps, whose order is specified:
(A) mixing at least one therapeutic agent suitable for topical administration to a mammalian patient and at least one component suitable for providing a carrier medium thereof to obtain a mixture thereof;
(B) cooling the mixture obtained in step (a) to substantially solidify it,
(C) molding at least a portion of the substantially solidified mixture obtained in step (b) to provide a substantially solid dosage form containing a unit dose of at least one therapeutic agent.
Other embodiments lead to a method of preparing a unit dose of a topical pharmaceutical formulation suitable for dermal administration to a mammalian patient:
(A) mixing the therapeutic agent with at least one pharmaceutically acceptable carrier medium to obtain a mixture thereof;
(B) cooling the mixture obtained in step (a) to a temperature of less than or equal to about 15 ° C., wherein the cooled mixture obtained in step (b) is for obtaining a unit dose of the semi-solid therapeutic agent. . The pharmaceutical formulation has a diffusion consistency suitable for application to the skin area of an animal patient at ambient temperature before application to the skin area of an animal patient.
Thus, the present invention provides a method for the manufacture of a pharmaceutical formulation for dermal administration to an animal patient containing a unit dose of at least one therapeutic agent, the method comprising:
(A) mixing at least one therapeutic agent with the carrier medium to obtain a mixture thereof;
(B) molding at least a portion of the mixture obtained in step (a) to obtain this pharmaceutical formulation.
More particularly, the present invention provides a method of preparing a pharmaceutical formulation for dermal administration of at least one therapeutic agent comprising a unit dose of at least one therapeutic agent and suitable for dermal administration to an animal patient, The process consists of:
(A) mixing at least one therapeutic agent with the carrier medium to obtain a mixture thereof;
(B) molding at least a portion of the mixture obtained in step (a), tableting and molding at least a portion of the mixture obtained in step (a), containing a unit dose of at least one therapeutic agent. A pharmaceutical formulation is provided.
[0014]
Further, a first aspect of the present invention provides a method for the manufacture of a pharmaceutical formulation for dermal administration of at least one therapeutic agent suitable for dermal administration to an animal patient, wherein the pharmaceutical formulation is typically at ambient temperature. A substantially solid dosage form having a softening point substantially below the skin temperature of an animal patient as described in more detail below, and containing a unit dose of at least one therapeutic agent. The process consists of:
(A) mixing at least one therapeutic agent with a majority of the carrier medium having a softening point below the skin temperature of the animal patient to obtain a mixture thereof;
(B) molding at least a portion of the mixture obtained in step (a) at a temperature below the softening point of the carrier medium, having a softening point below the skin temperature of the animal patient, and at least one unit of therapeutic agent It forms a substantially solid form (usually a substantially solid dosage form) containing the dose.
The shaping of the mixture of at least one therapeutic agent and the carrier medium substantially as described above, to provide a pharmaceutical formulation comprising a unit dose of the therapeutic agent, will usually involve substantially any step (as described above). It consists of tableting at least a part of the mixture obtained in a). Generally, "tabletting" as described herein involves introducing at least a portion of a mixture of at least one therapeutic agent and a carrier medium made according to the present invention into a tablet press and compressing the introduced mixture. To provide a substantially solid form. Generally, a substantially solid dosage form will have a size and form suitable for dermal administration of at least one therapeutic agent substantially as described herein. In fact, because they already form part of the state of the art, tablets containing therapeutic agents are manufactured by compressing a mixture of finely divided components in the common form of pharmaceutical preparations for oral delivery. It is known to be advantageous in view of the relative accuracy and reproducibility of the dosage, the desired handling characteristics and generally less expensive manufacturing processes. However, the tablets of the present invention for dermal administration of a unit dose of at least one therapeutic agent to animal patients do not form part of the state of the art, but are known tablets for oral administration substantially as described above. Have similar advantages.
[0015]
The method of manufacturing a pharmaceutical formulation of the present invention further comprises cooling at least a portion of the mixture of at least one therapeutic agent and its carrier medium, substantially as described above, to enhance the handling characteristics of the mixture by cooling. It can be improved and the rate of tableting as done by the present invention can also be increased. Substantially as described above, cooling may suitably be performed before and / or during molding of the mixture with the at least one therapeutic agent and its carrier medium. Preferably, the mixture is cooled to a temperature of less than or equal to about 15 ° C, advantageously less than or equal to about 10 ° C, eg, less than or equal to about 0 ° C, prior to and / or during molding, substantially as described above. Can be.
Suitably, the cooling as performed in the method of the present invention will be at least partially achieved by using a cooled tablet press. Advantageously, the mixture of at least one therapeutic agent and its carrier medium can be cooled before it is introduced into a tablet machine or the like.
[0016]
In a preferred method according to the first aspect of the present invention there is provided a method of preparing a pharmaceutical formulation for dermal administration of at least one therapeutic agent suitable for dermal administration to an animal patient, wherein the pharmaceutical formulation comprises at least one therapeutic agent. Having a substantially solid dosage form at ambient temperature and having the pharmaceutical formulation applied to the skin area of the animal patient to administer the unit dose of the therapeutic agent to the animal patient. It can soften to a consistency that can be absorbed by the area. The method consists of the following steps, in which the order is specified:
(A) mixing at least one therapeutic agent suitable for dermal administration to an animal patient and at least one component suitable for providing a carrier medium thereof to obtain a mixture thereof;
(B) cooling the mixture obtained in step (a) (preferably at a temperature of about 10 ° C. or less, preferably about 0 ° C. or less) to substantially solidify it;
(C) forming at least a portion of the substantially solidified mixture obtained in step (b), and forming a substantially solid form (usually a substantially solid agent) of the pharmaceutical formulation according to the first aspect of the present invention. Shape).
Typically, the method of the first aspect of the invention further comprises reducing the size of the particles (eg, by granulation, prilling, etc.) prior to forming into a substantially solid dosage form. The substantially solidified mixture obtained in step (b) may be suitably granulated to provide a plurality of particles in the size range of 100 to 1000 microns.
[0017]
Preferably, the pharmaceutical formulations provided herein will be substantially free of preservatives, as substantially described in more detail below. In such a case, the process of the present invention is preferably performed under aseptic conditions.
Further, it may be preferred that the pharmaceutical formulation as provided in the present invention is substantially free of antioxidants, substantially as described in more detail below. In such cases, when the method of the present invention involves packaging of a pharmaceutical formulation, at least such packaging is performed in a substantially inert atmosphere such as nitrogen or the like.
The invention also provides a pharmaceutical formulation comprising a unit dose of at least one therapeutic agent and a carrier vehicle thereof, wherein the pharmaceutical formulation is capable of dermally administering a unit dose of at least one therapeutic agent to an animal patient.
[0018]
According to a first aspect of the present invention as described above, there is further provided a pharmaceutical formulation for dermal administration of at least one therapeutic agent suitable for dermal administration to an animal patient, wherein the pharmaceutical formulation is substantially at ambient temperature. At least one therapeutic agent having a solid dosage form, having a softening point below the skin temperature of an animal patient (substantially as described in more detail below), and suitable for dermal administration to an animal patient Contains a unit dose of
More specifically, according to the first aspect of the invention described above, there is provided a pharmaceutical formulation for dermal administration of at least one therapeutic agent suitable for dermal administration to an animal patient, wherein the pharmaceutical formulation comprises It has a dosage form that is substantially solid at temperature and includes at least one therapeutic agent mixed with the carrier medium. The pharmaceutical formulation is characterized by a solid dosage form, which can be softened when applied to the skin area of an animal patient, so that after application to the skin area, the solid dosage form is treated by the animal patient. To administer a unit dose of the agent, it is softened to a consistency that can be substantially absorbed by the skin area.
Even more particularly, the first aspect of the invention described above provides a pharmaceutical formulation for dermal administration of at least one therapeutic agent suitable for dermal administration to an animal patient, wherein the pharmaceutical formulation is at ambient temperature. Has a substantially solid dosage form and comprises a unit dose of at least one therapeutic agent mixed with the carrier medium. The formulation is characterized by a substantially solid dosage form, which can soften upon application to the skin area of the animal patient, such that after application to the skin area, the solid dosage form In order to substantially completely administer the unit dose of the therapeutic agent to the patient, it is softened to a consistency that can be completely absorbed by the skin area.
[0019]
The substantially solid dosage form of the pharmaceutical formulation at ambient temperature according to the first aspect of the invention is usually provided in the form of a tablet, substantially as described above, and usually as substantially as described above. Manufactured. Alternatively, a substantially solid dosage form of the pharmaceutical formulation according to the first aspect of the invention will be provided in the form of a rolled preparation, for example a pill.
According to a first aspect of the present invention, the carrier medium, or more particularly the substantially solid dosage form, is at room temperature as described above, but substantially as described in more detail below, but may be at the skin temperature of an animal patient. At temperatures below the temperature (hereinafter referred to as the diffusion point), it may generally be preferred to convert to a diffusion consistency. In this case, it may further generally be preferred that the shaping step of the method according to the first aspect of the invention be performed at a temperature below the diffusion point of either the carrier medium or substantially the solid dosage form. Absent.
Generally, the carrier medium and more particularly the substantially solid dosage form of the pharmaceutical formulation according to the first aspect of the invention is softened, advantageously converted to a diffusion consistency at a temperature in the range of 30-37 ° C. Would be preferred. Thus, as described above, the formulation can be softened by application to the skin area of the animal patient, such that, after application, the substantially solid dosage form of the formulation provides the animal patient with the therapeutic agent. In order to substantially completely administer the unit dose, it is softened to a consistency which allows it to be absorbed substantially completely in the skin area.
[0020]
The pharmaceutical formulation of the first aspect of the invention, after application to the skin area, in less than about 10 minutes, preferably less than about 5 minutes, more preferably less than about 3 minutes, and most preferably less than about 1 minute, Substantially (preferably substantially completely) absorbed in the skin area of the animal patient to substantially (preferably substantially completely) administer the unit dose of the at least one therapeutic agent to the animal patient. It is particularly preferred to have a substantially solid dosage form at ambient temperature that can soften to a consistency that can be achieved.
More particularly, the shape and form of the substantially solid dosage form is preferably measured at its softening point, substantially as described herein. The substantially solid dosage form used in the formulation of the invention may consist of a single dosage form, or the substantially solid dosage form used in the formulation of the invention may be substantially as described above. It may be preferable to be able to consist of a plurality of substantially separated substantially solid particles (such as a plurality of granules) that can be absorbed by the skin of the animal patient. Where the substantially solid dosage form used in the formulations of the present invention can consist of substantially discrete particles as described herein, such discrete particles are substantially described herein. It may be appropriate to include a closure (eg, capsule, sachet, blister package, etc.) that can be dispensed and applied to the patient's skin.
[0021]
Also, the substantially solid dosage form carrier medium of the pharmaceutical formulation according to the first aspect of the present invention is suitable for shaping at a temperature of about ambient temperature or higher for incorporation of the formulation into a substantially solid dosage form. It may be preferred to be further characterized by In one aspect of the invention, the carrier medium of the substantially solid dosage form of the formulation according to the first aspect of the invention comprises a substantially solid formulation of the formulation at a temperature of less than 10 ° C, preferably less than 0 ° C. It may be preferable to be further characterized by being suitable for molding for incorporation into a shape. More specifically, the substantially solid dosage form of the carrier medium is suitable for tableting at a temperature of less than 10 ° C., preferably less than 0 ° C., using techniques substantially as described herein. It may be preferred to be further characterized by
Preferably, the carrier medium comprises at least about 60% by weight, more preferably at least about 80% by weight, even more preferably at least about 90% by weight, based on the weight of the pharmaceutical formulation according to the first aspect of the invention.
[0022]
Any base component commonly used in suppositories can be used as the base component in the pharmaceutical formulations of the present invention, including those derived from animal, vegetable or mineral sources, and partially or wholly synthesized materials. Specific examples of such base components are oils and fats of animal or vegetable origin, such as olive oil, corn oil, castor oil, cottonseed oil, malt oil, cocoa butter, hydrogenated oil, etc .; hydrocarbons such as squalane, petrolatum And waxes such as jojoba oil, carnauba wax, beeswax, lanolin and the like. As partially or wholly synthesized fatty acid ester glycerol, mono-, di- or triglycerides of saturated linear fatty acids, such as vehicles such as lauric acid, myristic acid, palmitic acid, stearic acid or higher fatty acids, or, for example, And unsaturated linear fatty acids such as oleic acid, linoleic acid and linolenic acid. Commercially available products of these base components include Witepsol (manufactured by Dynamit Nobel), Pharmasol (manufactured by Nippon Oil & Fat Co., Ltd.), Isocacao (manufactured by Kao Corporation), and (Taiyo Yushi Co., Ltd.) (Made by Henkel), Supposire (made by Gattefosse), and the like. Polyethylene glycols, such as macrogol, setmacrogol, and the like, and derivatives thereof, such as setocrogol, are examples of other synthetic products.
[0023]
A base can be combined with another base to increase or decrease the softening point, if necessary, to obtain a desired softening point of the pharmaceutical formulation of the present invention, to obtain a suitable product. . For example, a base suitable as a plasticizer, such as glyceryl monoacetate, myristyl alcohol, polysorbate 80, propylene glycol, or a combination thereof, can be added to reduce the softening point. Bases suitable as hardeners for increasing the softening point, for example beeswax, cetyl alcohol, stearic acid, stearyl alcohol, aluminum monostearate, aluminum distearate, aluminum tristearate, bentonite, magnesium stearate, colloid Silicon dioxide and combinations thereof can be added.
[0024]
A carrier medium for use in accordance with the first aspect of the invention is substantially as described above, for example, at least one therapeutic suitable for use in tablets substantially as described above and suitable for dermal administration. It may contain any ingredient suitable for use in pharmaceutical preparations, such as any ingredient having the desired properties for dermal administration of a unit dose of the agent. For example, the carrier medium may comprise cellulose and one or more components selected from the group consisting of components of a type suitable for the use of suppositories (eg, one or more glycerol esters of saturated fatty acids or one or more polyethers). One or more glycerides, such as glycolylated glycerides, including cocoa butter, theobroma, etc., one or more high molecular weight polyethylene glycols, one or more polyoxyethylenes, lanolin and derivatives thereof, and one or more fatty acids, Fatty alcohols, fatty acid esters (eg, including caprylic acid, tricapryl glyceryl, etc.), and one or more organic oils (eg, including hydrogenated vegetable oils) may be included.
The carrier medium used in the pharmaceutical formulation according to the first aspect of the present invention may especially comprise one or more C8-C18It is often preferred to include or consist essentially of one or more glycerides containing glycerol esters of fatty acids or one or more polyglycolized glycerides.
[0025]
Suitably, the carrier medium of the pharmaceutical formulation according to the first aspect of the invention comprises or consists essentially of a mixture of glycerides, if the glycerides can be one or more monoglycerides, diglycerides or triglycerides. Suitably, the glyceride mixture is such that the glyceride is C12-C18It may comprise glycerides selected from the group consisting of monoglycerides, diglycerides and triglycerides, which are glycerol esters of fatty acids, with Witepsol grade products being suitable. More specifically, the carrier medium is a trade name of Witepsol H5, Witepsol H15, Witepsol H32, Witepsol S51, Witepsol S55, Witepsol S58, Witepsol W25 and Witepsol W32 It comprises or consists essentially of a Witepsol grade product available at either. Particularly preferred Witepsol grade products for use as carrier vehicles in pharmaceutical formulations according to the present invention are available under any of the trade names Witepsol H5, Witepsol H15, Witepsol S51, and Witepsol S55 It is possible and in particular available under the trademark Witepsol H15.
[0026]
It is often preferred that the carrier medium used in the medicament according to the first aspect of the invention consist essentially of a Witepsol grade product substantially as described above.
Alternatively, the carrier medium of the pharmaceutical formulation according to the first aspect of the invention comprises or consists essentially of a mixture of glycerides, wherein the glycerides can be selected from the group consisting of monoglycerides, diglycerides and triglycerides;8-C18Glycerol esters of fatty acids or one or more polyglycolized glycerides. Suitably, such glyceride mixtures are available under the trade names Gelucire or Suppocire, and are usually the following Gescia 33/01, Gescia 39/01, Gescia 43/01, Gescia 43/01. 14 or any of the Saposia standard type, Saposia N type or Saposia P type products.
Alternatively, a carrier medium suitable for use in a pharmaceutical formulation according to the first aspect of the invention comprises or consists essentially of cocoa butter.
[0027]
Active agents that can be used in the present invention include all drugs that can be delivered on or through the skin for either local or systemic action. These compounds provide ACE inhibitors, pituitary hormones, adrenergic neuron blockers, inhibitors of corticosteroid biosynthesis, α-adrenergic agonists, α-adrenergic antagonists in all major treatment areas. Drugs, selective α-2-adrenergic drugs, analgesics, antipyretics and anti-inflammatory drugs, androgens, local and general anesthetics, anti-addiction drugs, anti-androgens, anti-arrhythmic drugs, anti-asthmatic drugs, anti-cholinergic drugs, Anticholinesterase agent, anticoagulant, antidiabetic, antidepressant, antidiuretic, antiemetic and prokinetic agent, antiepileptic, antiestrogen, antifungal, antihypertensive, antibacterial, anti Migraine, antimuscarinic, antitumor, antiparasitic, antiparkinsonian, antiplatelet, antiprogestin, antithyroid, Cough medicine, antiviral medicine, atypical antidepressant medicine, azaspirodecanione, barbiturate, benzodiazepine, benzothiadiazide, β-adrenergic agonist, β-adrenergic antagonist, selective β-1-adrenergic agonist, selection Β-2-adrenergic agonists, bile salts, drugs affecting body fluid volume and composition, butyrophenone, drugs affecting calcification, calcium antagonists, cardiovascular drugs, catecholamines and sympathomimetics, cholinergic drugs , Cholinesterase reactivating drug, dermatological agent, diphenylbutylpiperidine, diuretic, ergot alkaloid, estrogen, ganglion blocker, ganglion stimulant, hydantoin, gastric acidity regulator and peptic ulcer treatment drug, hematopoietic agent , Histamine, histamine antagonist, 5-hydroxytryptamine antagonist, high liposome Remedies for proteinemia, sleeping pills and sedatives, immunosuppressants, laxatives, methylxanthine, monoamine oxidase inhibitors, neuromuscular blockers, organic nitrates, pancreatic enzymes, phenothiazines, progestins, prostaglandins, remedies for mental disorders , Retinoids, sodium channel blockers, agents for spastic paralysis and acute muscle spasm, succinimide, thioxanthine, thrombolytics, thyroid, tricyclic antidepressants, inhibitors of tubular transport of organic compounds, affects uterine motility Includes but is not limited to drugs, including drugs, vasodilators, vitamins, and the like.
[0028]
By way of example, representative drugs include bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil, dobutamine, isoproterenol, cartelolol, labetalol, levobanolol, nadolol, penbutrol, pindolol, propranolol, sotalol. , Timolol, Acebutolol, Atenolol, Betaxolol, Esmolol, Metoprolol, Albuterol, Bitolterol, Isoethalin, Metaproterenol, Pirbuterol, Litodrine, Terbutaline, Alclomethasone, Aldosterone, Amcinonide, Beclomethasone, Dipropionate, Thipropionate, Thipropionate, Thipropionate Costosterone, de Nide, desoxymethasone, 11-deoxycorticosterone, 11-desoxyoxycortisol, dexamethasone, diflorazone, fludrocortisone, flunisolide, fluocinolone, fluocinonide, fluorometholone, flulandrenolide, halcinonide, hydrocortisone, medrizone, 6alpha -Methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tetrahydrocortisol, triamcinolone, benoxynate, benzocaine, bupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine, etidocaine, lidocaine, mepivacaine, pramocaine, prilocaine, procacaine, prilocaine, prolocaine Fentanyl, coloform, clonidine, cyclopropane Desflurane, diethyl ether, droperidol, enflurane, etomidate, halothane, isoflurane, ketamine hydrochloride, meperidine, methohexital, methoxyflurane, morphine, propofol, sevoflurane, thiamylal, thiopental, acetaminophen, allopurinol, apazone, aspirin, auranofin, Aurothioglucose, colchicine, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, sodium gold thiomalate, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meseramine, methyl salicylate, nabumeton, naproxen, oxyfenbuta Dzone, phenacetin, phenylbutazone, piroxicam, salicylamin , Salicylate, salicylic acid, salsalate, sulfasalazine, sulindac, tolmetin, acetophenazine, chlorpromazine, fluphenazine, mesoridazine, perphenazine, thioridazine, trifluoroperazine, triflupromazine, disopyramide, encainide, flecainide, indecinide, meximedin Phenytoin, procainamide, propafenone, quinidine, tocainide, cisapride, domperidone, dronabinol, haloperidol, metoclopramide, nabilone, prochlorperazine, promethazine, thiethylperazine, trimethobenzamide, buprenorphine, butorphanol, dezocin, diphenoxylate, drocodex Hydrocodone, hydromorphone, levallorphan, levo Phanol, loperamide, meptazinol, methadone, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone, oxybutynin, pentazocine, isosorbide dinitrate, nitroglycerin, theophylline, phenylephrine, efidrine, pilocarpine, furosemide, tetracycline, chlorpheniraklamine, chlorpheniramine troquinprin, chlorpheniramine Including but not limited to prazosin, doxazosin and flufenamic acid.
[0029]
Other representative drugs are benzodiazepines such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepate, demoxeppam, diazepam, flumazenil, flurazepam, harazepam, lorazepam, midazolam, nitrazepamazepam, oxazepam, nordazepam, oxazepam, nordazepam, nordazepam Antimuscarinic agents such as anisotropin, atropine, clidinium, cyclopentolate, dicyclomine, flavoxate, glycopyrrolate, hexocyclium, homatropine, ipratropium, isopropamide, mepenzolate, methanthelin, oxyphencyclimine, pirenzepine, propantheline , Scopolamine, telenzepine, tridihexetil, tropicamide, etc. Estrogens, for example, chlorotrianisene, cyethylstilbestrol, methylestradiol, estrone, sodium estrone sulfate, estropipate, mestranol, quinestrol, sodium equilin sulfate, 17β-estradiol (or estradiol), for example, estradiol-17β-enanthate Estradiol-17β-valerate, estradiol-3-benzoate, estradiol-17β-undesenoate, semi-synthetic estrogen derivatives such as esters of natural estrogens such as estradiol 16,17-hemisuccinate or estradiol-17β-cypionate, and ethinyl estradiol; Ethinylestradiol-3-isopropyl sulfonic acid Androgens such as danazol, fluoxymesterone, metandrostenolone, methyltestosterone, nandrolone decanoate, nandrolone fenpropionate, oxandrolone, oxymetholone, stanozolol, test lactone, and the like. Testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate and the like; or a progestin such as ethinodiol diacetate, gestodene, hydroxyprogesterone caproate, levonorgestrel, medroxyprogestes acetate, megestrol acetate, norethindrone, acetate Including norethindrone, norethynodrel, norgestrel, progesterone and the like.
[0030]
In embodiments where the active drug produces a local effect, the agent may be an antiviral agent (eg, acyclovir and idoxuridine, etc.), an antifungal agent (eg, amphotericin B, clotrimazole, nystatin, ketoconazole, micoronazole, butocourazole. , Haloprosin, etc.), antibiotics (penicillin, cephalosporin, erythromycin, tetracycline, clindamycin, aminoglycoside, chloramphenicol, polymyxin b, bacitracin, neomycin, gentamicin, etc.), preservatives (eg, povidone iodine, Methylbenzethonium chloride, etc.), anthelmintics (eg, lindane, anthralin, etc.), analgesics (eg, methyl salicylate, salicylic acid, diclonin, aloe, etc.), local anesthetics (eg, benzocaine, lidocaine) Anti-inflammatory agents (eg, dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, alclomethasone, amcinonide, diflorazone, etc. and non-steroidal anti-inflammatory drugs), anti-scabies and inflammation Palliative compounds (eg, antihistamines such as diphenhydramine and psoriasis treatments), burn soothing compounds (eg, o-amino-p-toluenesulfonamide, monoacetate, etc.), depigmenting agents (eg, monobenzone), and hormonal agents ( (For example, estriol), but is not limited to (and in addition to the above topical agents).
[0031]
Compounds that can be used in the present invention, including those listed above, are meant to include all pharmaceutically acceptable salts and conjugates.
Other topically active compounds are described in Remington's Pharmaceutical Sciences, 17th Edition, Merck Publishing Co. Easton, Pa .; (1985), pages 773-791 and 1054-1058 (hereinafter Remington), incorporated herein by reference.
Furthermore, the pharmaceutical preparations of the present invention can be used for cosmetic purposes, for example, for other uses such as antiperspirants, sunscreens, depilation, emollients, fragrances and anti-acne preparations.
These pharmaceutical preparations include sunscreens such as dimethylamino p-benzoate, emollients such as urea, keratolytics such as salicylic acid, acne agents such as benzoyl peroxide, fragrances and the like.
Suitable antiperspirant compositions contain astringent salts. Astringent salts include the organic and inorganic salts of aluminum, zirconium, zinc and mixtures thereof. The anion of the astringent salt may be, for example, nitrate, chloride, chlorohydroxide, alum, formate, lactate, benzylsulfonate or phenylsulfonate. Specific examples of antiperspirant astringent salts include aluminum halides, aluminum hydroxy halides, zirconyl oxyhalides, zirconyl hydroxy halides and mixtures thereof.
[0032]
Specific aluminum salts include aluminum chloride and aluminum hydroxy halide. Specific zirconium compounds include zirconium oxy salts and zirconium hydroxy salts, and are further referred to as zirconyl salts and zirconyl hydroxy salts.
Therefore, specific antiperspirant compounds are aluminum bromohydrate, potassium alum, sodium aluminum chlorohydroxylactate, aluminum sulfate, aluminum chlorohydrate, aluminum-zirconium tetrachlorohydrate, aluminum-zirconium polychloroform combined with glycine. Hydrate, aluminum-zirconium trichlorohydrate, aluminum-zirconium octachlorohydrate, aluminum sesquichlorohydrate, aluminum sesquichlorohydrex PG, aluminum chlorohydrex PEG, aluminum zirconium octachlorohydrex glycine complex, aluminum zirconium pentachloro Hydrex glycine complex, aluminum Ruconium tetrachlorohydrex glycine complex, aluminum zirconium trichlorohydrex glycine complex, aluminum chlorohydrex PG, zirconium chlorohydrate, aluminum dichlorohydrate, aluminum dichlorohydrex PEG, aluminum dichlorohydrex PG, aluminum sesquichlorohydrex Including but not limited to PG, aluminum chloride, aluminum zirconium pentachlorohydrate and mixtures thereof. Many other useful antiperspirant compounds are described in WO 91/19222 and the Cosmetic and Toiletry Fragrance Handbook, The Cosmetic, Toiletry and Fragrance Association, Inc., Washington. C. 56, 1989 (hereinafter referred to as the CTFA Handbook), which is incorporated herein by reference.
[0033]
The pharmaceutical formulation according to the first aspect of the invention is suitable for use with any therapeutic agent suitable for dermal administration, as substantially described in more detail below. However, the pharmaceutical formulation of the first aspect of the present invention is particularly suitable for dermal administration of at least one local anesthetic to animal patients, so that the pharmaceutical formulation of the first aspect of the present invention It may be preferable to include at least one local anesthetic, particularly lignocaine, also known as lidocaine, as the therapeutic agent to be administered. Alternatively, the pharmaceutical formulation of the first aspect of the present invention described above is particularly suitable for dermal administration of at least one corticosteroid to an animal patient, It may be preferable to include at least one corticosteroid (especially hydrocortisone) as the therapeutic agent to be administered dermally.
Accordingly, particularly preferred pharmaceutical formulations according to the first aspect of the present invention include pharmaceutical formulations for dermal administration of lignocaine to animal patients, wherein at ambient temperature a unit dose of lignocaine mixed with a carrier vehicle comprising Witepsol S55 Having a substantially solid dosage form. The pharmaceutical formulation is characterized by a solid dosage form, which can be softened when applied to the skin area of an animal patient, such that after application to the skin area, the substantially solid dosage form becomes To substantially (substantially completely) administer a unit dose of lignocaine to a patient, it is softened to a consistency that can be (substantially completely) absorbed by the skin area.
[0034]
Particularly preferred alternative formulations according to the first aspect of the invention include formulations for dermal administration of hydrocortisone to animal patients, comprising a unit dose of hydrocortisone mixed at ambient temperature with a carrier medium consisting essentially of cocoa butter. It has a substantially solid dosage form. The formulation is characterized by a substantially solid dosage form, which can soften when applied to the skin area of an animal patient, such that after application to the skin area, the substantially solid dosage form is: In order to substantially (substantially completely) administer a unit dose of hydrocortisone to the animal patient, it is softened to a consistency that can be (substantially completely) absorbed by the skin area.
Still more particularly preferred alternative formulations according to the first aspect of the invention include formulations for the dermal administration of hydrocortisone to animal patients, wherein the hydrocortisone is mixed at ambient temperature with a carrier medium consisting essentially of Witepsol H15. Has a substantially solid dosage form containing a unit dose of The formulation is characterized in a substantially solid dosage form and, after application to the skin area, a substantially solid dosage form is applied to the animal patient by being able to soften when applied to the animal patient. To substantially (substantially completely) administer a unit dose of hydrocortisone, it is converted to a consistency that can be (substantially completely) absorbed by the skin area.
[0035]
According to the first aspect of the invention described above, the invention substantially as described above with a covering member which can be arranged to substantially cover the pharmaceutical formulation when applied to the skin area of an animal patient. There is further provided means for applying a drug comprising the pharmaceutical preparation of the first aspect of the present invention and a coated member thereof to the skin area of an animal patient.
Preferably, the product of the first aspect of the invention is substantially as described above with a substantially soft substrate suitable for substantially covering the pharmaceutical formulation when applied to the skin area of an animal patient. Provided in the form of a transdermal patch for medical use containing the pharmaceutical preparation of the first aspect of the present invention. The substrate has an adhesive means (usually in the form of a sticky coating applied thereto) for applying it to the skin area of the animal patient. Since the patch can be applied to the skin area of the animal patient, it is brought into contact with the skin such that the temperature of the substantially solid dosage form rises above its softening point to a consistency that can be absorbed by the skin. Thus, a substantially solid dosage form of the formulation is maintained, resulting in the administration of a unit dose of the therapeutic to the animal patient.
Suitable patch substrates as provided in the first aspect of the invention do not substantially penetrate the formulation. Suitably, the substrate may be a polymer film of a type suitable for use in conventional plasters.
[0036]
In an alternative embodiment of the product according to the first aspect of the invention described above, the product is a plastic film-like, although the covering member is arranged to overlap the formulation in use when applied to the skin of the patient. The spacing from the applied formulation may create a localized, moist atmosphere near the skin area where the formulation is applied. Thus, a moist localized atmosphere can help soften a substantially solid dosage form for absorption by the patient's skin.
As substantially described in greater detail below, when the therapeutic agent is for the treatment of a local condition of the skin, substantial absorption by at least the outer epidermal layer of the skin of the animal patient is sufficient for the treatment of the patient. Yes, a substantial percutaneous route to the bloodstream is required, but it will be appreciated that in practice it may be undesirable in some cases.
For example, one or more tableting aids, flow aids (eg, silicon dioxide, etc.) and compaction aids (eg, microcrystalline cellulose, dicalcium phosphate, etc.) which may be selected from anti-adhesives (eg, talc, etc.). Or any other ingredient suitable for use in a pharmaceutical formulation as a tableting aid and a method according to the first aspect of the invention as described above, and a medicament according to the first aspect of the invention substantially as described above. It may be advantageous to use the formulation, and consequently, its production method of the invention.
The present invention further comprises a unit dose of at least one therapeutic agent, substantially as described in greater detail below, at ambient temperature to the skin area of the animal patient prior to application to the skin area of the animal patient. By providing a formulation having a suitable diffusion consistency for application of the formulation, after application, the formulation will be absorbed to administer a unit dose of the therapeutic agent.
[0037]
Accordingly, the present invention further relates to the provision of an ointment or cream containing a unit dose of at least one therapeutic agent, substantially as described in greater detail below, for dermal administration to an animal patient.
Thus, according to a second aspect of the present invention, prior to application to the skin area of an animal patient, a formulation having a diffusion consistency suitable for application to the skin area of an animal patient at ambient temperature (ie, Ointment and creamy formulations at ambient temperature), comprising at least one therapeutic agent and its carrier medium substantially as described above with respect to the method according to the first aspect of the invention. After the mixture has been produced and shaped, it consists of reaching a temperature at which the mixture has a diffusional consistency (this temperature is here referred to as the diffusion point of the formulation according to the invention and is described in more detail below). .
Typically, in the method of the second aspect of the present invention, during forming at least a portion of the mixture substantially as described above, at a temperature below ambient temperature and usually below about 15 ° C, advantageously below about 10 ° C. For example, a substantially solid that is substantially converted to a diffusion consistency at a temperature of about 0 ° C. or less is produced.
[0038]
In the method according to the second aspect of the invention, the substantially solid form is at a temperature below the diffusion point of the pharmaceutical formulation and usually below about 15 ° C, advantageously below about 10 ° C, for example below about 0 ° C. It is generally preferred to produce by molding at temperature.
According to a particular embodiment of the second aspect of the invention, it comprises a unit dose of at least one therapeutic agent suitable for dermal administration to an animal patient and, prior to application to the skin area of the animal patient, the ambient temperature. Thus, there is provided a method for producing a pharmaceutical preparation having a diffusion consistency suitable for application to the skin area of an animal patient. The method consists of:
(A) mixing at least one therapeutic agent and at least one carrier medium therefor to obtain a mixture thereof;
(B) molding at least a portion of the mixture obtained in step (a) at a temperature of about 15 ° C. or less.
The step of shaping is advantageously performed at a temperature of about 10 ° C. or less, for example, about 0 ° C. or less, substantially as described above. Advantageously, the part shaped as obtained in step (b) is packaged substantially as described in more detail below, for example in individual closed containers therefor, and then packaged The portion can suitably be substantially warmed to ambient temperature.
Thus, preferably, the method of the second aspect of the present invention further comprises the step of substantially warming the substantially solid to its diffusion point (ie, the substantially solid (Prior to reaching the temperature at which it is to be converted), packaging the substantially solid form produced substantially as described above. Thus, a packaged dose, as described in greater detail below, and more particularly a substantially separate plurality of packaged doses of the formulation, can be provided according to the second aspect of the invention. Such a packaged dose or a separate packaged dose of a pharmaceutical formulation according to the second aspect of the invention in the form of a cream or ointment is easy to handle and apply by the patient or attending physician and at the same time one or more to be administered by it. A relatively accurate dosing of the therapeutic agent is also possible.
[0039]
Particularly preferred steps according to the second aspect of the invention consist of the following, in which the order is specified:
(A) mixing at least one therapeutic agent and its carrier medium suitable for dermal administration to an animal patient to obtain a mixture thereof;
(B) cooling the mixture obtained in step (a) (preferably at a temperature of about 10 ° C. or less, preferably about 0 ° C. or less) to substantially solidify it;
(C) forming at least a portion of the substantially solidified mixture obtained in step (b) (usually at a temperature of less than about 15 ° C, advantageously less than about 10 ° C, for example less than about 0 ° C); ), Providing a substantially solid form,
(D) The resulting substantially solid form obtained in step (c) is allowed to reach ambient temperature and is converted to a diffuse consistency.
As substantially described herein, it will be preferred that the pharmaceutical formulation as provided herein is substantially free of preservatives, as substantially described in more detail below. In such a case, the method of the present invention is preferably performed under aseptic conditions.
[0040]
Further substantially as described herein, it may be preferred that the pharmaceutical formulation as provided herein is substantially free of antioxidants, as substantially described in more detail below. Absent. In such cases, if the method of the present invention involves the packaging of a pharmaceutical formulation, such packaging is preferably performed in a substantially inert atmosphere such as nitrogen or the like.
According to a second aspect of the invention, the animal patient contains a unit dose of at least one therapeutic agent suitable for dermal administration to an animal patient, and is applied at ambient temperature to the animal patient prior to application to the skin area of the animal patient. Further provided is a pharmaceutical formulation having a diffusion consistency suitable for application to the skin area.
More particularly, there is also provided an ointment or cream comprising a unit dose of at least one therapeutic agent suitable for dermal administration to an animal patient and a majority of the carrier medium, wherein the ointment or cream has a diffusion point below ambient temperature. Have.
Furthermore, it consists of a plurality of separate doses of the pharmaceutical formulation according to the second aspect of the invention, each dose having a diffusion consistency at a temperature below the skin temperature of the animal patient, and more particularly, usually at ambient temperature diffusion. Provided are agents having a diffusion consistency at a temperature of less than or equal to about 15 ° C., for example, less than or equal to about 10 ° C., more generally.
[0041]
According to a particularly preferred embodiment of the second aspect of the present invention there is provided a pharmaceutical formulation for dermal administration of at least one therapeutic agent suitable for dermal administration to an animal patient, wherein each of the agents comprises at least one therapeutic agent. Consists of a number of separate doses containing the agent, each dosage form comprising:
A unit dose of at least one therapeutic agent and
Prior to application to the skin area of an animal patient, at ambient temperature, a carrier medium having a diffusion consistency suitable for application to the skin area
Consisting of a mixture containing
Thereby, after application to the skin area of the animal patient, the dose can be substantially (substantially completely) absorbed in the skin area of the animal patient, and the animal patient can be substantially dosed with a unit dose of the therapeutic agent. (Substantially completely) administered.
Preferably, the carrier medium as used in the pharmaceutical formulation according to the second aspect of the invention, and more particularly, the pharmaceutical formulation according to the second aspect of the invention may have a diffusion point below about 15 ° C. Advantageously, the carrier medium as used in the pharmaceutical formulation according to the second aspect of the invention, more particularly the pharmaceutical formulation according to the second aspect of the invention, has a diffusion point below about 10 ° C, for example below about 0 ° C. May have. Thus, such a pharmaceutical formulation according to the second aspect of the invention may have a diffusion point below ambient temperature. It will be appreciated that if the diffusion point is below ambient temperature, the pharmaceutical formulation will not be solid when stored or applied at ambient temperature. Generally, such a pharmaceutical formulation will be manufactured as a substantially solid formulation at a temperature substantially below the diffusion point as described above, but after refilling substantially as described above. Alternatively, it may be warmed to a temperature above the diffusion point.
[0042]
Preferably, the carrier medium comprises at least about 60%, more preferably at least about 80% and even more preferably at least about 90% by weight, based on the weight of the pharmaceutical formulation of the second aspect of the invention.
The carrier medium for use in the pharmaceutical formulation according to the second aspect of the present invention may be substantially any suitable substance acceptable for skin use as described above. For formulations that are to be creamed at the skin temperature, the carrier medium may include an emulsion. For formulations that are to be in the form of an ointment at skin temperature, the carrier medium may include oils.
Suitable carrier media for use in the pharmaceutical preparations of the present invention include suppositories (eg, one or more glycerides such as one or more glycerol esters of saturated fatty acids or one or more polyglycolized glycerides, cocoa butter, cyanobroma, and the like). 1) one or more high molecular weight polyethylene glycols, one or more polyoxyethylenes, lanolin and derivatives thereof, one or more fatty acids, fatty alcohols, fatty acid esters (including, for example, caprylic acid, tricapryl glyceryl, etc.) and It may be selected from the group consisting of components of a type suitable for use in such organic oils (eg, containing hydrogenated vegetable oils) and the like.
A particularly suitable carrier medium for use in the pharmaceutical formulation according to the second aspect of the invention is substantially a complete mixture of cocoa butter and at least one organic oil such as, for example, castor oil or tonsil oil. Become.
The present invention provides a method for administering a unit dose of at least one therapeutic agent suitable for dermal administration to an animal patient as described herein to the animal patient, wherein the formulation is substantially as described above. Further provided is a method of treating an animal patient by dermal administration.
[0043]
More specifically, the present invention provides a method of dermally administering at least one therapeutic agent to an animal patient, wherein the therapeutic agent is provided by a pharmaceutical formulation of the first aspect of the present invention substantially as described above. The method of administration consists of:
Applying a substantially solid dosage form of a pharmaceutical formulation according to the first aspect of the present invention to the skin area of an animal patient substantially as described above;
Maintaining the applied pharmaceutical formulation in contact with the animal patient's skin area to soften the substantially solid dosage form to a consistency that can be (substantially completely) absorbed by the animal patient's skin area ,
Thereby, a unit dose of the therapeutic agent is (substantially completely) administered to the animal patient.
The invention further provides a method of dermally administering at least one therapeutic agent to an animal patient, wherein the therapeutic agent is provided in a pharmaceutical formulation according to the second aspect of the invention substantially as described above. Consists of:
Applying the pharmaceutical formulation of the second aspect of the invention substantially as described above to the skin area of the animal patient (usually applying the medicament of the second aspect of the invention substantially as described above to an animal patient); By applying at least one therapeutic agent suitable for dermal administration)
Substantially as described above, by substantially rubbing the applied formulation (or at least one applied discrete dose) of the second aspect of the present invention substantially as described above into the skin area of the animal patient. Such an applied formulation (or at least one applied discrete dose) according to the second aspect of the invention may be (substantially completely) absorbed by the skin,
Thereby, a unit dose of the therapeutic agent is (substantially completely) administered to the animal patient.
[0044]
According to the present invention there is further provided a pharmaceutical formulation substantially as hereinbefore described for use in the manufacture of a medicament for dermal administration to an animal patient, wherein the pharmaceutical formulation or substantially any one of the Examples herein is provided. Also provided are medicaments as described in.
The term “therapeutic agent” as used herein is suitable for dermal administration to animal patients (especially humans) and (in either the first or second aspect of the invention) relates to any pharmaceutical formulation or product of the invention. Any active substance suitable for the use of the present invention, and any such active substance that can be administered dermally as described above to exert the desired pharmacological therapeutic effect on the body of an animal (especially a human). May be usually contained. As used herein, the term "therapeutic agent" refers to any pharmaceutically acceptable equivalent thereof such as, for example, a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof. In addition. All isomers of the disclosed agents are also included by this disclosure.
As used herein, the term “dermal administration” or “skin administration” refers to (i) use in the present invention for the local or topical treatment of a dermatological disorder as substantially described in more detail below. For the administration of suitable therapeutic agents and (ii) for non-topical treatment, ie for administration to the bloodstream of an animal (especially a human) patient for systemic therapy substantially as described in more detail below. And the administration of therapeutic agents suitable for use in the present invention.
[0045]
The term "treatment" as used herein refers to the treatment of a chronic condition and its prevention. The exact therapeutic state of any pharmaceutical formulation, medicament or method according to the present invention will, of course, depend on the exact nature of the condition to be treated, the age and sex of the animal (especially human) patient and, in the end, the judgment of the attending physician Will be left behind.
As noted above, therapeutics for use in accordance with the present invention may have local (which is often preferred) or non-local activity.
Therapeutic agents having local activity for use according to any aspect of the present invention include, for example, agents used in the treatment of skin disorders. By way of example, such diseases include psoriasis, eczema, acne, diaper rash and other inflammatory diseases of the skin, bacterial or fungal infections of the skin, malignant diseases of the skin, warts and the like.
Advantageously, the therapeutic agent having local activity for use according to the invention is selected from the group consisting of a local anesthetic, a corticosteroid, an antibacterial agent, an antifungal agent or any therapeutically effective combination thereof. Can be.
More particularly, therapeutic agents having local activity for use in accordance with the present invention include tetracaine, benzocaine, lignocaine, hydrocortisone, beclomethasone, diproprionate, clobetasol propionate, fluticasone propionate, icutamol, lithium succinate, coal tar, Consist of dithranol, benzoyl peroxide, tretinoin, sulfur, vitamin D and their derivatives, framycetin, chlortetracycline hydrochloride, fusidic acid, clotrimazole, econazole, amorolfine and turbenafine or any therapeutically effective combination thereof You can choose from groups.
The present invention is particularly suitable for effecting local delivery of lignocaine or hydrocortisone as substantially described in more detail below.
[0046]
Therapeutic agents having non-local activity for use according to any aspect of the present invention include, for example, the treatment or prevention of various systemic diseases and their symptoms, such as cardiovascular diseases, muscle or joint abnormalities, organ diseases. Including active substances used for More particularly, therapeutic agents having non-local activity for use according to any aspect of the invention include, for example, agents used as vasodilators, agents for treating motion sickness, contraceptives, hormone replenishers, analgesics And smoking cessation aids or any therapeutically effective combination thereof.
The therapeutic agent having non-local activity for use according to any aspect of the invention is advantageously selected from the group consisting of nitroglycerin, scopolamine, estradiol, norethisterone, fentanyl and nicotine or any therapeutically effective combination thereof. Is done.
Therapeutic agents used in the present invention should be present in a therapeutically effective concentration, eg, at least 0.01% by weight based on the total weight of the pharmaceutical formulation. Generally, the therapeutic agent is less than 10% by weight, advantageously less than 2% by weight, more advantageously less than 5% by weight, preferably less than 1% by weight, more preferably less than 0.1% by weight, based on the total weight of the pharmaceutical formulation. It will be present in an amount up to 05% by weight.
Suitably, the pharmaceutical formulations of the present invention may, if appropriate, further comprise additional components such as, for example, one or more curing agents, one or more plasticizers. Suitable hardeners include, for example, beeswax, cetyl alcohol, stearic acid, stearyl alcohol, aluminum monostearate, bentonite, and the like. Suitable plasticizers include, for example, glyceryl monostearate, ministil alcohol, polysorbate 80, propylene glycol, and the like.
Suitably, the pharmaceutical formulations of the present invention may, if appropriate, be, for example, one or more penetration enhancers for therapeutic agents (surfactants, alcohols, esters, glycols, etc. or any other suitable penetration synergist). ), Wetting agents, surfactants (which may be cationic, nonionic, anionic or polymeric), emulsifiers, antioxidants, preservatives, clay, defoamers, spreading agents, skin Additional components such as emollients, barriers, solubilizers and the like may be further included.
[0047]
However, in certain aspects of the invention, it is generally preferred that the pharmaceutical formulations of the invention are substantially free of preservatives of the type generally included in pharmaceutical formulations for dermal administration, or for dermal administration May contain at least the amount of such preservatives usually less than or equal to the amount normally required for the preparation of the formulation, or generally cause a substantial allergic reaction in susceptible patients as substantially described below. Preferably, it will contain at least some such amount of preservatives. Such preservatives commonly used in formulations for dermal administration are present to prevent contamination of such dermatological formulations and are obtained in the present invention, as such formulations are repeatedly handled. Depending on the possible unit dose on the skin, it may not be necessary in the present invention. In fact, the use of such preservatives to obviate contamination with frequent handling is detrimental, as in some patients an allergic reaction occurs in susceptible patients, and the invention is susceptible to disease. It may be beneficial to prevent such allergic reactions in the patient. Preservatives associated with allergic reactions include chlorocresol, hydroxybenzoate (paraben), polysorbate, sorbic acid, and the like, for example, the following registered trademarks, Drapolene, Medicaid, Siopel, Sprion (Sprilon), Aulux, Efcortelan, Mildison, Fucidin H, Nystafrom, Quinocoat, Terra-Nortin (Terra-Cortil). Nystatin), Timodine, Locoid, Locoid Crelo, Moco Radson (Modrasone), Propaderm (Propaderm), Vietnovate (Betnovate), Vietnomate RD (Betnovate RD), Diprosone (Diprosone), Delmovate (Dermovate), Eumovate (Temovanate, Eumovate) ), Synalar, Ultraranum Plain, Zorac, Carbo-Dome, Exorex, Exorex, Differin, Excelderm, etc. May be present in many prior art topical formulations, including available formulations It is known.
[0048]
However, the pharmaceutical formulation of the present invention further comprises one or more preservatives, such as phenoxyethanol and the like, which are commonly included during manufacture to substantially prevent contamination of the pharmaceutical formulation of the present invention, as described above. As such, they are not of the kind generally used to prevent infection.
It is further preferred that the pharmaceutical formulations of the present invention will be substantially free of oxidative preservatives of the type commonly contained in formulations for dermal administration, or in amounts normally required for formulations for dermal administration. An amount of an oxidative preservative that may include at least the following such oxidative preservatives, or that does not generally cause a substantial allergic reaction in a patient susceptible to disease as substantially described below: It may be preferable to include at least something like Such oxidative preservatives, commonly used in formulations for dermal administration, are commonly present to prevent the fat present in such rancid formulations, and are effective for general storage and use Will be present mainly to prevent oxidation after opening. Such oxidative preservatives may not be necessary in the present invention, or at least are necessary to a lesser extent than used in prior art formulations, depending on the unit dose on the skin that can be obtained with the present invention. Or, more specifically, it may be used at a concentration that does not normally cause a substantial allergic reaction in susceptible patients. The use of such antioxidants is detrimental in some patients because they cause an allergic reaction in susceptible patients, and the present invention obviates such allergic reactions in susceptible patients So it might be useful. Antioxidants associated with allergic reactions include butylhydroxyanisole, butylhydroxytoluene, and the like, and are known in the art, such as those formulations available under any of the registered trademarks, such as Imuderm, Siopel, and the like. Is known to be available in topical formulations.
[0049]
The term "softening point" as used herein, as described above, is used in a pharmaceutical formulation according to the first aspect of the invention to administer a unit dose of a therapeutic agent in the pharmaceutical formulation to a patient. The temperature at which a substantially solid dosage form begins to soften to a consistency that can be absorbed by the patient's skin.
The "softening point" of a substantially solid dosage form of a pharmaceutical formulation according to the first aspect of the invention, substantially as described above, is the viscosity at which the substantially solid dosage form can be absorbed by the skin of the patient. It can be measured visually as the temperature at which it begins to soften to consistency, and as such, is advantageously substantially complete on the patient's skin, so as to leave substantially no undesirable residue on the patient's skin. Can be absorbed.
Advantageously, the "softening point" of the substantially solid dosage form of the pharmaceutical formulation according to the first aspect of the invention substantially as described above is a TA-XT2 texture suitably equipped with a 5 kg weigh scale. It can be measured using an analyzer. The device is placed in a temperature controlled chamber (operable in the range of -60C to 200C). A tablet or other substantially solid dosage form of the present invention may be in the chamber at a specified temperature for at least 10 minutes. A 3 mm planar probe is pressed into the tablet or other substantially solid dosage form of the invention at 1 mm intervals at a rate of 0.1 mm / sec.
The measurement can be repeated at an increasing temperature of 1 ° C. and the recorded maximum resistance (as measured by Texture Excess software) is the resistance of the “solid” tablet or other substantially solid dosage form of the invention. At temperatures falling below 50% of the force, tablets or other dosage forms are considered to "soften".
[0050]
The term "diffusion point" as used herein with respect to a pharmaceutical formulation according to either the first or second aspect of the invention may, for example, flow out under the weight of the formulation itself, or may be used, e. Refers to the temperature at which a formulation that can be spread at least lightly on the skin has a "diffuse" consistency. The fluidity of a formulation having a diffuse consistency will move the therapeutic agent toward the skin, for example, to facilitate absorption of the therapeutic agent into the skin by diffusion. The diffusion point of the formulation may be measured using the TA-XT2 texture analyzer described above with respect to measuring the softening point, and the diffusion point of the formulation can be measured using this analyzer to allow the planar probe to enter the preparation. Is the temperature at which external outflow of the formulation is first observed before it is released.
The term "unit dose" means a formulation suitable for single administration containing, for example, an effective amount of the agent to be administered, such as a therapeutically active agent or a cosmetic agent.
The pharmaceutical preparation of the present invention can be packaged in a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. Generally, blister packs consist of a sheet of relatively rigid material, preferably covered with a foil of transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recess has the size and shape of the formulation to be packaged. The pharmaceutical preparation of the present invention can be placed in a recess and a sheet of relatively hard material is sealed against a plastic foil on the foil surface opposite to the direction in which the recess was formed. As a result, the formulation is sealed with a recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the formulation can be manually pressed into the recess and removed from the blister pack so that the opening allows the location of the recess without affecting the entire formulation. Formed on the sheet. In other embodiments, the foil can be peeled. Therefore, the preparation of the present invention can be removed through the opening.
[0051]
For example, it may be desirable to provide a memory aid on the blister pack in a number that corresponds to the number of regulatory days that the formulation so specified should be applied. Another example of such a memory aid is a calendar printed on a card such as, for example, "First week, Monday, Tuesday, etc., Second week, Monday, Tuesday", etc. . Various other memory aids will be readily apparent. A "daily dose" can be one formulation or several formulations to be applied on a given day.
The pharmaceutical preparations of the present invention are preferably in solid form during the final manufacturing process and packaging, preferably at the time of administration.
The present invention will now be further illustrated by the following examples, which are not intended to limit the invention in any way.
[0052]
Example 1
Tablet ingredients:
Lignocaine 2%
Tween 62 (emulsifier) $ 5%
Witepsol @ S55*93%
*Low dissolution (33-35 ° C.) triglyceride.
Percentage ratios are weights based on the total weight of the combined components.
Production method:
1.混合 Mix the ingredients in a high shear mixer blender for 5 minutes to form a granular mixture. The mixture was immersed in dry ice contained in a container and cooled.
2. Tablets were compressed with a Manesty F compressor using a 10 mm flat zirconia tool. The mixture was condensed under compression and then solidified to form tablets.
[0053]
Example 2
Tablet ingredients:
Hydrocortisone 0.005g
Cocoa butter 0.275g
Production method:
The cocoa butter was gradually dissolved until uniformly dissolved. Next, hydrocortisone was added and mixed while gradually heating. The mixture was cooled and then allowed to cure in the refrigerator overnight. Once cured, the solids were crushed and granulated.
Tablets were compressed with TA-XT2 using a 10 mm flat stainless steel / zirconia tool. The mixture was condensed under compression and then solidified to form tablets.
[0054]
Example 3
Tablet ingredients:
Hydrocortisone 0.005g
Witepsol H15 0.334 g
Production method:
Witepsol H15 was gradually dissolved until homogeneously dissolved. Next, hydrocortisone was added and mixed while gradually heating. The mixture was cooled and then allowed to cure in the refrigerator overnight. Once cured, the solids were crushed and granulated.
Tablets were compressed with TA-XT2 using a 10 mm flat stainless steel / zirconia tool. The mixture was condensed under compression and then solidified to form tablets.
[0055]
Example 4
Dosage components
Hydrocortisone
Carrier
Four different carrier formulations were used at dosages prepared according to Example 4 as follows.
Formulation 1:
50% castor oil
50% cocoa butter
Formulation 2:
60% castor oil
40% cocoa butter
Formulation 3:
70% castor oil
30% cocoa butter
Formulation 4:
70% tonsil oil
30% cocoa butter
[0056]
Production method
The cocoa butter and the selected oil as described in Formulations 1-4 were slowly dissolved until homogeneously dissolved. Next, hydrocortisone was added and mixed while gradually heating. The mixture was cooled and then allowed to cure in the refrigerator. Once cured, the solids were broken and then granulated at low temperature.
The dose was prepared by compressing with TA-XT2 using a 10 mm flat stainless steel / zirconia tool. The mixture was condensed and solidified under compression at a temperature of 0-4 ° C to reach room temperature and form a substantially softened solid dose.
Claims (122)
(b)ステップ(a)で得られた混合物の少なくとも一部を成形し、1:1(壁面:表面)より低いアスペクト比を有する固形状製剤を得、その結果生じた医薬製剤が、哺乳動物の皮膚温度以下の軟化点を有し、哺乳動物患者の皮膚と連続して接触させておいた時、10分未満の時間内に治療剤の単位用量を哺乳動物患者の所望の皮膚面積に実質的に塗布するための粘稠度に軟化される
ことからなり、少なくとも1つの治療剤の単位用量を含有する動物患者に皮膚投与するための医薬製剤の製造方法。(A) mixing at least one therapeutic agent and its carrier medium to obtain a mixture thereof;
(B) molding at least a portion of the mixture obtained in step (a) to obtain a solid formulation having an aspect ratio of less than 1: 1 (wall: surface), wherein the resulting pharmaceutical formulation is a mammal Having a softening point below the skin temperature of the subject, and when in continuous contact with the skin of the mammalian patient, the unit dose of the therapeutic agent is substantially reduced to the desired skin area of the mammalian patient within less than 10 minutes. A method for the manufacture of a pharmaceutical formulation for dermal administration to an animal patient, comprising a unit dose of at least one therapeutic agent, which comprises being softened to a consistency for topical application.
(b)担体媒体の軟化点以下の温度で、ステップ(a)で得られた混合物の少なくとも一部を成形し、哺乳動物患者の皮膚温度以下の軟化点を有し、少なくとも1つの治療剤の単位用量を含有する実質的に固形状のものを形成する
ことからなり、哺乳動物患者の皮膚温度以下の軟化点を有し、少なくとも1つの治療剤の単位用量を含有する動物患者への局所投与に適した少なくとも1つの治療剤を局所投与するための医薬製剤の製造方法。(A) mixing at least one therapeutic agent that is not suitable for topical administration to a mammalian patient with a majority of its carrier medium having a softening point below the skin temperature of the mammalian patient to obtain a mixture thereof;
(B) forming at least a portion of the mixture obtained in step (a) at a temperature below the softening point of the carrier medium, having a softening point below the skin temperature of the mammalian patient, Topical administration to an animal patient having a softening point below the skin temperature of a mammalian patient and containing a unit dose of at least one therapeutic agent, comprising forming a substantially solid form containing the unit dose. A method for the manufacture of a pharmaceutical formulation for topical administration of at least one therapeutic agent suitable for:
(a)哺乳動物患者への局所投与に適した少なくとも1つの治療剤およびその担体媒体の提供に適した少なくとも1つの成分を混合して、それらの混合物を得、
(b)ステップ(a)で得られた混合物を冷却して、をれを実質的に凝固させ、
(c)ステップ(b)で得られた実質的に凝固した混合物の少なくとも一部を成形し、少なくとも1つの治療剤の単位用量を含有する実質的に固形状の剤形を提供する
ことからなり、治療剤の単位用量を含有し、周囲温度で実質的に固形状の剤形を有し、哺乳動物患者に治療剤の単位用量を投与するために、哺乳動物患者の皮膚面積にそれを塗布した時に皮膚面積で吸収され得る粘稠度に軟化し得る哺乳動物患者への局所投与に適した少なくとも1つの治療剤を局所投与するための医薬製剤の製造方法。The following steps, in which the order is specified:
(A) mixing at least one therapeutic agent suitable for topical administration to a mammalian patient and at least one component suitable for providing a carrier medium thereof to obtain a mixture thereof;
(B) cooling the mixture obtained in step (a) to substantially solidify the particles;
(C) shaping at least a portion of the substantially solidified mixture obtained in step (b) to provide a substantially solid dosage form containing a unit dose of at least one therapeutic agent. Containing a unit dose of the therapeutic agent, having a substantially solid dosage form at ambient temperature, and applying it to the skin area of the mammalian patient to administer the unit dose of the therapeutic agent to the mammalian patient A method for the manufacture of a pharmaceutical formulation for topical administration of at least one therapeutic agent suitable for topical administration to a mammalian patient, which may be softened to a consistency that can be absorbed by the skin area when exposed.
(d)ステップ(a)で得られた混合物を約15℃以下の温度に冷却し、
(e)ステップ(b)で得られた冷却混合物は半固形状該治療剤の単位用量を得るためのものであり、その製剤が動物患者の皮膚面積に塗布する前に、周囲温度で、動物の患者の皮膚面積への塗布に適した拡散粘稠度を有する
ことからなり、哺乳動物患者への皮膚投与に適した局所医薬製剤の単位用量の製造方法。(C) mixing the therapeutic agent with at least one pharmaceutically acceptable carrier medium to obtain a mixture thereof;
(D) cooling the mixture obtained in step (a) to a temperature of about 15 ° C. or less;
(E) the chilled mixture obtained in step (b) is for obtaining a unit dose of the therapeutic agent in semi-solid form, wherein the formulation is applied to the animal at ambient temperature before application to the skin area of the animal patient. A method for producing a unit dose of a topical pharmaceutical formulation suitable for dermal administration to a mammalian patient, having a diffusion consistency suitable for application to the skin area of a patient.
(b)製剤を患者の皮膚面積で塗布および/または吸収され得る粘稠度に軟化するために、患者の皮膚面積に接触させてステップ(a)の塗布された医薬製剤を維持する
ことからなる請求項1〜4、9および28のいずれかによる医薬製剤で提供される少なくとも1つの治療剤を哺乳動物患者に皮膚投与する方法。(A) applying the formulation to the skin area of a mammalian patient,
(B) maintaining the applied pharmaceutical formulation of step (a) in contact with the patient's skin area to soften the formulation to a consistency that can be applied and / or absorbed on the patient's skin area 29. A method of dermally administering to a mammalian patient at least one therapeutic agent provided in a pharmaceutical formulation according to any of claims 1-4, 9 and 28.
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GBGB0015617.4A GB0015617D0 (en) | 2000-06-26 | 2000-06-26 | Improved preparations for dermal delivery of active substances |
PCT/GB2001/002823 WO2002000203A1 (en) | 2000-06-26 | 2001-06-26 | Topical pharmaceutical formulations and methods of treatment |
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CN112237547B (en) * | 2020-09-28 | 2022-08-30 | 安徽美邸康药业有限公司 | Medicine subsides forming device |
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